Five-membered heterocycles useful as serine protease inhibitors

ABSTRACT

The present invention provides a method for treating a thrombotic or an inflammatory disorder administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula (I) or Formula (V): 
                         
or a stereoisomer or pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L, Z, R 3 , R 4 , R 6 , R 11 , X 1 , X 2 , and X 3  are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also provides compounds within the scope of Formula I and relates to pharmaceutical compositions comprising these compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.14/219,311, filed Mar. 19, 2014, now allowed, which is a divisional ofU.S. application Ser. No. 13/326,809, filed Dec. 15, 2011, now U.S. Pat.No. 8,716,492, which is a divisional of U.S. application Ser. No.12/209,235, filed Sep. 12, 2008, now U.S. Pat. No. 8,101,778, which is adivisional of U.S. application Ser. No. 11/151,667, filed Jun. 13, 2005,now U.S. Pat. No. 7,453,002, which claims the priority benefit of U.S.Provisional Application No. 60/579,638, filed Jun. 15, 2004 and thepriority benefit of U.S. Provisional Application No. 60/684,127, filedMay 24, 2005, all of which are expressly incorporated fully herein byreference.

FIELD OF THE INVENTION

The present invention provides a method for treating a thrombotic or aninflammatory disorder administering to a patient in need thereof atherapeutically effective amount of at least one compound of Formula (I)or Formula (V):

or a stereoisomer or pharmaceutically acceptable salt or solvate formthereof, wherein the variables A, L, Z, R³, R⁴, R⁶, R¹¹, X¹, X², and X³are as defined herein. The compounds of Formula (I) are useful asselective inhibitors of serine protease enzymes of the coagulationcascade and/or contact activation system; for example thrombin, factorXa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. Inparticular, it relates to compounds that are selective factor XIainhibitors or dual inhibitors of fXIa and plasma kallikrein. Thisinvention also relates to pharmaceutical compositions comprising thesecompounds and methods of using the same.

BACKGROUND OF THE INVENTION

Factor XIa is a plasma serine protease involved in the regulation ofblood coagulation. While blood coagulation is a necessary and importantpart of the regulation of an organism's homeostasis, abnormal bloodcoagulation can also have deleterious effects. For instance, thrombosisis the formation or presence of a blood clot inside a blood vessel orcavity of the heart. Such a blood clot can lodge in a blood vesselblocking circulation and inducing a heart attack or stroke.Thromboembolic disorders are the largest cause of mortality anddisability in the industrialized world.

Blood coagulation is initiated in vivo by the binding of tissue factor(TF) to Factor VII (FVII) to generate Factor VIIa (FVIIa). The resultingTF:FVIIa complex activates Factor IX (FIX) and Factor X (FX) which leadsto the production of Factor Xa (FXa). The FXa that is generatedcatalyzes the transformation of prothrombin into small amounts ofthrombin before this pathway is shut down by tissue factor pathwayinhibitor (TFPI). The process of coagulation is then further propagatedvia the feedback activation of Factors V, VIII and XI by catalyticamounts of thrombin. (Walsh, P. N., Thromb. Haemost., 82:234-242(1999).) Factor XIa plays a key role in propagating this amplificationloop and is thus an attractive target for anti-thrombotic therapy.

An alternative way of initiation of coagulation is operative when bloodis exposed to artificial surfaces (e.g., during hemodialysis, ‘on-pump’cardiovascular surgery, vessel grafts, bacterial sepsis). This processis also termed contact activation. Surface absorption of factor XIIleads to a conformational change in the factor XII molecule, therebyfacilitating activation to proteolytic active factor XII molecules(factor XIIa and factor XIIf). Factor XIIa (or XIIf) has a number oftarget proteins, including plasma prekallikrein and factor XI. Activeplasma kallikrein further activates factor XII, leading to anamplification of contact activation. Contact activation is a surfacemediated process responsible in part for the regulation of thrombosisand inflammation, and is mediated, at least in part, by fibrinolytic-,complement-, kininogen/kinin-, and other humoral and cellular pathways(for review, Coleman, R., Contact Activation Pathway, pp. 103-122, inHemostasis and Thrombosis, Lippincott Williams & Wilkins (2001);Schmaier A. H., Contact Activation, pp. 105-128, in Thrombosis andHemorrhage (1998)).

Factor XI is a zymogen of a trypsin-like serine protease and is presentin plasma at a relatively low concentration. Proteolytic activation atan internal R369-1370 bond yields a heavy chain (369 amino acids) and alight chain (238 amino acids). The latter contains a typicaltrypsin-like catalytic triad (H413, D464, and S557). Activation offactor XI by thrombin is believed to occur on negatively chargedsurfaces, most likely on the surface of activated platelets. Plateletscontain high affinity (0.8 nM) specific sites (130-500/platelet) foractivated factor XI. After activation, factor XIa remains surface boundand recognizes factor IX as its normal macromolecular substrate.(Galiani, D., Trends Cardiovasc. Med., 10:198-204 (2000).)

In addition to the feedback activation mechanisms described above,thrombin activates thrombin activated fibrinolysis inhibitor (TAFI), aplasma carboxypeptidase that cleaves C-terminal lysine and arginineresidues on fibrin, reducing the ability of fibrin to enhancetissue-type plasminogen activator (tPA) dependent plasminogenactivation. In the presence of antibodies to FXIa, clot lysis can occurmore rapidly independent of plasma TAFI concentration. (Bouma, B. N. etal., Thromb. Res., 101:329-354 (2001). Thus, inhibitors of factor XIaare expected to be anticoagulant and profibrinolytic.

Genetic evidence indicates that factor XI is not required for normalhomeostasis, implying a superior safety profile of the factor XImechanism compared to competing antithrombotic mechanisms. In contrastto hemophilia A (factor VIII deficiency) or hemophilia B (factor IXdeficiency), mutations of the factor XI gene causing factor XIdeficiency (hemophilia C) result in only a mild to moderate bleedingdiathesis characterized primarily by postoperative or posttraumatic, butrarely spontaneous hemorrhage. Postoperative bleeding occurs mostly intissue with high concentrations of endogenous fibrinolytic activity(e.g., oral cavity, and urogenital system). The majority of the casesare fortuitously identified by preoperative prolongation of APTT(intrinsic system) without any prior bleeding history.

The increased safety of inhibition of XIa as an anticoagulation therapyis further supported by the fact that Factor XI knock-out mice, whichhave no detectable factor XI protein, undergo normal development, andhave a normal life span. No evidence for spontaneous bleeding has beennoted. The APTT (intrinsic system) is prolonged in a gene dose-dependentfashion. Interestingly, even after severe stimulation of the coagulationsystem (tail transection), the bleeding time is not significantlyprolonged compared to wild-type and heterozygous litter mates.(Gailiani, D., Frontiers in Bioscience, 6:201-207 (2001); Gailiani, D.et al., Blood Coagulation and Fibrinolysis, 8:134-144 (1997). Takentogether, these observations suggest that high levels of inhibition offactor XIa should be well tolerated. This is in contrast to genetargeting experiments with other coagulation factors.

In vivo activation of factor XI can be determined by complex formationwith either C1 inhibitor or alpha 1 antitrypsin. In a study of 50patients with acute myocardial infarction (AMI), approximately 25% ofthe patients had values above the upper normal range of the complexELISA. This study can be viewed as evidence that at least in asubpopulation of patients with AMI, factor XI activation contributes tothrombin formation (Minnema, M. C. et al., Arterioscler. Thromb. Vasc.Biol., 20:2489-2493 (2000)). A second study establishes a positivecorrelation between the extent of coronary arteriosclerosis and factorXIa in complex with alpha 1 antitrypsin (Murakami, T. et al.,Arterioscler. Thromb. Vasc. Biol., 15:1107-1113 (1995)). In anotherstudy, Factor XI levels above the 90th percentile in patients wereassociated with a 2.2-fold increased risk for venous thrombosis(Meijers, J. C. M. et al., N. Engl. J. Med., 342:696-701 (2000)).

Plasma kallikrein is a zymogen of a trypsin-like serine protease and ispresent in plasma at 35 to 50 μg/mL. The gene structure is similar tothat of factor XI, overall, the amino acid sequence of plasma kallikreinhas 58% homology to factor XI. Proteolytic activation by factor XIIa atan internal I 389-R390 bond yields a heavy chain (371 amino acids) and alight chain (248 amino acids). The active site of kallikrein iscontained in the light chain. The light chain of plasma kallikreinreacts with protease inhibitors, including alpha 2 macroglobulin andC1-inhibitor. Interestingly, heparin significantly accelerates theinhibition of plasma kallikrein by antithrombin III in the presence ofhigh molecular weight kininogen (HMWK). In blood, the majority of plasmakallikrein circulates in complex with HMWK. Kallikrein cleaves HMWK toliberate bradykinin. Bradykinin release results in increase of vascularpermeability and vasodilation (for review, Coleman, R., ContactActivation Pathway, pp. 103-122, in Hemostasis and Thrombosis,Lippincott Williams & Wilkins (2001); Schmaier A. H., ContactActivation, pp. 105-128, in Thrombosis and Hemorrhage (1998)).

Proteins or peptides that reportedly inhibit Factor XIa are disclosed inWO 01/27079. There are advantages in using small organic compounds,however, in preparing pharmaceuticals, e.g., small compounds generallyhave better oral bioavailability and compatibility in makingformulations to aid in delivery of the drug as compared with largeproteins or peptides. Small molecule inhibitors of Factor XIa aredisclosed in U.S. Publication No. 2004/0235847 A1 and U.S. PublicationNo. 2004/0220206 A1.

Moreover, it is also desirable to find new compounds with improvedpharmacological characteristics compared with known serine proteaseinhibitors. For example, it is preferred to find new compounds withimproved factor XIa inhibitory activity and selectivity for factor XIaversus other serine proteases. Also, it is preferred to find newcompounds with improved plasma kallikrein inhibitory activity andselectivity for plasma kallikrein versus other serine proteases. It isalso desirable and preferable to find compounds with advantageous andimproved characteristics in one or more of the following categories, butare not limited to: (a) pharmaceutical properties; (b) dosagerequirements; (c) factors which decrease blood concentrationpeak-to-trough characteristics; (d) factors that increase theconcentration of active drug at the receptor; (e) factors that decreasethe liability for clinical drug-drug interactions; (f) factors thatdecrease the potential for adverse side-effects; and (g) factors thatimprove manufacturing costs or feasibility.

SUMMARY OF THE INVENTION

The present invention provides novel five-membered heterocyclederivatives, and analogues thereof, which are useful as selectiveinhibitors of serine protease enzymes, especially factor XIa and/orplasma kallikrein, or stereoisomers or pharmaceutically acceptablesalts, solvates, or prodrugs thereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or a stereoisomer or apharmaceutically acceptable salt, solvate, or prodrug form thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt, solvate or prodrug formthereof.

The present invention also provides a method for modulation of thecoagulation cascade and/or the contact activation system comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt, solvate, or prodrugform thereof.

The present invention also provides a method for treating thromboembolicdisorders comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt, solvate, orprodrug form thereof.

The present invention also provides a method for treating inflammatorydiseases disorders comprising administering to a host in need of suchtreatment a therapeutically effective amount of at least one of thecompounds of the present invention or a pharmaceutically acceptablesalt, solvate, or prodrug form thereof.

The present invention also provides novel five-membered heterocyclederivatives, and analogues thereof, for use in therapy.

The present invention also provides the use of five-membered heterocyclederivatives, and analogues thereof, for the manufacture of a medicamentfor the treatment of a thromboembolic disorder.

The present invention also provides the use of five-membered heterocyclederivatives, and analogues thereof, for the manufacture of a medicamentfor the treatment of an inflammatory disorder.

These and other embodiments, which will become apparent during thefollowing detailed description, have been achieved by the inventors'discovery that the presently claimed novel compounds of the presentinvention, or pharmaceutically acceptable salt or prodrug forms thereof,are effective factor XIa inhibitors and/or plasma kallikrein inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention includes, inter alia, acompound of Formula (I):

or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

A is C₃₋₁₀ carbocycle substituted with 0-1 R¹ and 0-3 R², or a 5- to12-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-1 R¹ and 0-3 R²; provided when A is a heterocyclecontaining one or more nitrogen atoms, A is not attached to L via any ofthe nitrogen atoms on the A ring;

L is —C(O)NR¹⁰—, —NR¹⁰C(O)—, —CH₂C(O)NR¹⁰—, —CH₂NR¹⁰C(O)—,—C(O)NR¹⁰CH₂—, —NR¹⁰C(O)CH₂—, —S(O)₂NR¹⁰—, —NR¹⁰S(O)₂—, —CH₂S(O)₂NR¹⁰—,—CH₂NR¹⁰S(O)₂—, —S(O)₂NR¹⁰CH₂—, —NR¹⁰S(O)₂CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂NR⁷—, —NR⁷CH₂—, —CH₂CH₂NR⁷—, —NR⁷CH₂CH₂, —CH₂NR⁷CH₂—, —CH₂O—,—OCH₂—, —CH₂S(O)_(p)—, —S(O)pCH₂—, —CH₂CH₂O—, —OCH₂CH₂—, —CH₂OCH₂—,—CH₂CH₂S(O)_(p)—, —S(O)_(p)CH₂CH₂—, —CH₂S(O)_(p)CH₂—, —CH₂C(O),—CH₂C(O)CH₂—, —CH₂CH₂C(O)—, —C(O)CH₂CH₂—, or —C(O)CH₂—;

R¹ is, independently at each occurrence, —NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —C(═NH)NH₂, —C(O)NR⁸R⁹, —S(O)_(p)NR⁸R⁹,—(CH₂)_(r)NR⁷R⁸, —(CH₂)_(r)NR⁷CO₂R^(a), —CH₂NH₂, —CH₂NH(C₁₋₃ alkyl),—CH₂N(C₁₋₃ alkyl)₂, —CH₂CH₂NH₂, —CH₂CH₂NH(C₁-C₃ alkyl), —CH₂CH₂N(C₁₋₃alkyl)₂, —CH(C₁₋₄ alkyl)NH₂, —C(C₁₋₄ alkyl)₂NH₂, —C(═NR^(8a))NR⁷R⁸,—NHC(═NR^(8a))NR⁷R⁸, ═NR⁸, —NR⁸CR⁸(═NR^(8a)), F, Cl, Br, I, OCF₃, CF₃,—(CH₂)_(r)OR^(a), —(CH₂)_(r)SR^(a), CN, 1-NH₂-1-cyclopropyl, or C₁₋₆alkyl substituted with 0-1 R^(1a);

R^(1a) is H, —C(═NR^(8a))NR⁷R⁸, —NHC(═NR^(8a))NR⁷R⁸, —NR⁸CH(═NR^(8a)),—NR⁷R⁸, —C(O)NR⁸R⁹, F, OCF₃, CF₃, OR^(a), SR^(a), CN, —NR⁹SO₂NR⁸R⁹,—NR⁸SO₂R^(c), —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, or —(CF₂)_(r)CF₃;

R² is, independently at each occurrence, H, ═O, F, Cl, Br, I, OCF₃, CF₃,CHF₂, CN, NO₂, OR^(a), SR^(a), —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —S(O)₂NR⁸R⁹, —NR⁸S(O)₂R^(c),—S(O)R^(c), or —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(2a), C₂₋₆alkenyl substituted with 0-2 R^(2a), C₂₋₆ alkynyl substituted with 0-2R^(2a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(2b), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(2b);

R^(2a) is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸,CN, OCF₃, CF₃, OR^(a), SR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸SO₂R^(c), —S(O)R^(c), or —S(O)₂R^(c);

R^(2b) is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸,CN, NO₂, OR^(a), SR^(a), —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸,—C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —S(O)₂NR⁸R⁹, —S(O)₂R^(c), —NR⁸SO₂NR⁸R⁹,—NR⁸SO₂R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄ haloalkoxy-;

alternately, when R¹ and R² groups are substituted on adjacent ringatoms, they can be taken together with the ring atoms to which they areattached to form a 5- to 7-membered carbocycle or heterocyclecomprising: carbon atoms and 0-4 heteroatoms selected from N, O, andS(O)_(p), wherein said carbocycle or heterocycle is substituted with 0-2R^(2b);

R³ is —(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(r)C(O)NR⁸(CH₂)_(s)CO₂R^(3b),—(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3R^(3a) and 0-1 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(3a) and0-1 R^(3d);

R^(3a) is, independently at each occurrence, ═O, F, Cl, Br, I, OCF₃,CF₃, NO₂, CN, —(CH₂)_(r)OR^(3b), —(CH₂)_(r)SR^(3b), —(CH₂)_(r)NR⁷R⁸,C(═NR^(8a))NR⁸R⁹, —NHC(═NR^(8a))NR⁷R⁸, —NR⁸CR⁸(═NR^(8a)),—(CH₂)_(r)NR⁸C(O)R^(3b), ═NR⁸, —(CH₂)_(r)NR⁸C(O)R^(3b),—(CH₂)_(r)NR⁸C(O)₂R^(3b), —(CH₂)_(r)S(O)_(p)NR⁸R⁹,—(CH₂)_(r)NR⁸S(O)_(p)R^(3c), —S(O)_(p)R^(3c), —S(O)_(p)R^(3c),—C(O)—C₁-C₄ alkyl, —(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)OC(O)NR⁸R⁹, —NHCOCF₃, —NHSO₂CF₃, —SO₂NHR^(3b), —SO₂NHCOR^(3c),—SO₂NHCO₂R^(3c), —CONHSO₂R^(3c), —NHSO₂R^(3c), —CONHOR^(3b), C₁₋₄haloalkyl, C₁₋₄ haloalkoxy-, C₁₋₆ alkyl substituted by R^(3d), C₂₋₆alkenyl substituted by R^(3d), C₂₋₆ alkynyl substituted by R^(3d), C₃₋₆cycloalkyl substituted by 0-1 R^(3d), —(CH₂)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(3d);

alternately, when two R^(3a) groups are located on adjacent atoms, theycan be taken together with the atoms to which they are attached to forma C₃₋₁₀ carbocycle substituted with 0-2 R^(3d) or a 5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-2R^(3d);

R^(3b) is, independently at each occurrence, H, C₁₋₆ alkyl substitutedwith 0-2 R^(3d), C₂₋₆ alkenyl substituted with 0-2 R^(3d), C₂₋₆ alkynylsubstituted with 0-2 R^(3d), —(CH₂)—C₃₋₁₀ carbocycle substituted with0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(3d);

R^(3c) is, independently at each occurrence, C₁₋₆ alkyl substituted with0-2 R^(3d), C₂₋₆ alkenyl substituted with 0-2 R^(3d), C₂₋₆ alkynylsubstituted with 0-2 R^(3d), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(3d);

R^(3d) is, independently at each occurrence, H, ═O, —(CH₂)_(r)OR^(a), F,Cl, Br, CN, NO₂, —(CH₂)_(r)NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷C(O)R^(b), —C(O)NR⁸R⁹, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂R^(c),—S(O)_(p)R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e),C₂₋₆ alkenyl substituted with 0-2 R^(e), C₂₋₆ alkynyl substituted with0-2 R^(e), —(CH₂)_(r)C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d);

R⁴ is H, F, Cl, Br, I, OCF₃, CF₃, OR^(a), SR^(a), CN, NO₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkylsubstituted with 0-2 R^(4a), C₂₋₆ alkenyl substituted with 0-2 R^(4a),C₂₋₆ alkynyl substituted with 0-2 R^(4a), —(CH₂)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(4b), or —(CH₂)_(r)-5- to 10-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(4b);

R^(4a) is, independently at each occurrence, H, F, ═O, C₁₋₆ alkyl,OR^(a), SR^(a), CF₃, CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)₂R^(c),—S(O)R^(c), or —S(O)₂R^(c);

R^(4b) is, independently at each occurrence, H, ═O, ═NR⁸, F, Cl, Br, I,OR^(a), SR^(a), CN, NO₂, CF₃, —SO₂R^(c), —NR⁷R⁸, —C(O)R^(a),—C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,C₁₋₄ haloalkyl, or C₁₋₄ haloalkoxy-;

alternately, R³ and R⁴ groups when located on adjacent atoms, can betaken together to form a C₃₋₁₀ carbocycle substituted with 0-2 R^(3d) ora 5- to 10-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(3d);

R⁶ is H;

R⁷ is, independently at each occurrence, H, C₁₋₆ alkyl, —(CH₂)—C₃₋₁₀carbocycle, —(CH₂)_(n)(5-10 membered heteroaryl), —C(O)R^(c), —CHO,—C(O)₂R^(c), —S(O)₂R^(c), —CONR⁸R^(c), —OCONHR^(c), —C(O)O—(C₁₋₄alkyl)OC(O)—(C₁₋₄ alkyl), or —C(O)O—(C₁₋₄ alkyl)OC(O)—(C₆₋₁₀ aryl);wherein said alkyl, carbocycle, heteroaryl, and aryl are optionallysubstituted with 0-2 R^(f);

R⁸ is, independently at each occurrence, H, C₁₋₆ alkyl,—(CH₂)_(r)-phenyl, or —(CH₂)_(n)-5-10 membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);wherein said alkyl, phenyl and heterocycle are optionally substitutedwith 0-2 R^(f);

alternatively, R⁷ and R⁸, when attached to the same nitrogen, combine toform a 5- to 10-membered heterocyclic ring comprising carbon atoms and0-2 additional heteroatoms selected from N, O, and S(O)_(p), whereinsaid heterocycle is substituted with 0-2 R^(d);

R^(8a) is, independently at each occurrence, H, OH, C₁₋₆ alkyl, C₁₋₄alkoxy, (C₆₋₁₀ aryl)-C₁₋₄ alkoxy, —(CH₂)_(n)-phenyl, —(CH₂)_(n)—(5-10membered heteroaryl), —C(O)R^(c), —C(O)₂R^(c), —C(O)O—(C₁₋₄alkyl)OC(O)—(C₁₋₄ alkyl), or —C(O)O—(C₁₋₄ alkyl)OC(O)—(C₆₋₁₀ aryl);wherein said phenyl, aryl, and heteroaryl is optionally substituted with0-2 R^(f);

R⁹ is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(r)-phenyl; wherein said alkyl and phenyl are optionallysubstituted with 0-2 R^(f);

R^(9a) is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl;

alternatively, R⁸ and R⁹, when attached to the same nitrogen, combine toform a 5- to 10-membered heterocyclic ring comprising carbon atoms and0-2 additional heteroatoms selected from N, O, and S(O)_(p), whereinsaid heterocycle is substituted with 0-2 R^(d);

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-3 R^(10a), C₂₋₆ alkenyl substituted with 0-3 R^(10a), C₂₋₆ alkynylsubstituted with 0-3 R^(10a), —(CH₂)_(r)C₃₋₁₀ carbocycle substitutedwith 0-3 R^(d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(d);

R^(10a) is, independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a),SR^(a), F, CF₃, CN, NO₂, —C(O)OR^(a), —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸SO₂R^(c)—, —S(O)R^(c) or —S(O)₂R^(c);

R¹¹ is C₁₋₄ haloalkyl, —(CH₂)_(r)C(O)NR⁸R⁹, C₁₋₆ alkyl substituted with0-3 R^(11a), C₂₋₆ alkenyl substituted with 0-3 R^(11a), C₂₋₆ alkynylsubstituted with 0-3 R^(11a), —(CR¹⁴R¹⁵)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(11b), or —(CR¹⁴R¹⁵)_(r)-5- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p), wherein said heterocycle is substituted with 0-3R^(11b);

R^(11a) is, independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a),CF₃, SR^(a), F, CN, NO₂, —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —C(O)R^(a), —C(O)OR^(a),—S(O)_(p)R^(c), C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy-,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5-to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), and substituted with 0-3 R^(d);

R^(11b) is, independently at each occurrence, H, ═O, ═NR⁸, OR^(a), F,Cl, Br, CN, NO₂, CF₃, OCF₃, OCHF₂, —C(O)R^(a), —C(O)OR^(a), —SOR^(c),—SO₂R^(c), —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —NR⁸C(O)₂R^(c),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy-,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d);

alternately, when two R^(11b) groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-2R^(g);

R¹⁴ and R¹⁵ are, independently at each occurrence, H, F, or C₁₋₄ alkyl;

-   -   alternately, R¹⁴ combines with R¹⁵ to form ═O;

R^(a) is, independently at each occurrence, H, CF₃, C₁₋₆ alkyl,—(CH₂)_(r)—C₃₋₇ cycloalkyl, —(CH₂)_(r)—C₆₋₁₀ aryl, or —(CH₂)_(r)-5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p); wherein said cycloalkyl, aryl andheterocycle groups are optionally substituted with 0-2 R^(f);

R^(b) is, independently at each occurrence, CF₃, OH, C₁₋₄ alkoxy, C₁₋₆alkyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d);

R^(c) is, independently at each occurrence, CF₃, C₁₋₆ alkyl substitutedwith 0-2 R^(f), C₃₋₆ cycloalkyl substituted with 0-2 R^(f), C₆₋₁₀ aryl,5- to 10-membered heteroaryl, (C₆₋₁₀ aryl)-C₁₋₄ alkyl, or (5- to10-membered heteroaryl)-C₁₋₄ alkyl, wherein said aryl and heteroarylgroups are optionally substituted with 0-3 R^(f);

R^(d) is, independently at each occurrence, H, ═O, ═NR⁸, OR^(a), F, Cl,Br, I, CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁸C(O)R^(a), —C(O)NR⁷R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl,—NR⁸SO₂CF₃, —NR⁸SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl,—S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e),C₂₋₆ alkenyl substituted with 0-2 R^(e), or C₂₋₆ alkynyl substitutedwith 0-2 R^(e);

R^(e) is, independently at each occurrence, ═O, OR^(a), F, Cl, Br, I,CN, NO₂, —NR⁸R⁹, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁸C(O)R^(a),—C(O)NR⁷R⁸, —SO₂NR⁸R⁹, NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl, —NR⁸SO₂CF₃,—NR⁸SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, or—(CF₂)_(r)CF₃;

R^(f) is, independently at each occurrence, H, ═O, —(CH₂)_(r)—OR^(g), F,Cl, Br, I, CN, NO₂, —NR^(9a)R^(9a), —C(O)R^(g), —C(O)OR^(g),—NR^(9a)C(O)R^(g), —C(O)NR^(9a)R^(9a), —SO₂NR^(9a)R^(9a),—NR^(9a)SO₂NR^(9a)R^(9a), —NR^(9a)SO₂—C₁₋₄ alkyl, —NR^(9a)SO₂CF₃,—NR^(9a)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl,—(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, or—(CH₂)_(n)-phenyl;

R^(g) is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl;

n, at each occurrence, is selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is selected from 0, 1, and 2;

r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and

s, at each occurrence, is selected from 1, 2, 3, and 4;

provided that:

(a) when L is —C(O)NH—, R³ is not 2,4-dichlorophenyl, 4-nitrophenyl orpentafluorophenyl;

(b) when L is —C(O)NH—, R¹¹ is not —CH₂-(3-indolyl), —(CH₂)₄NHCO₂(t-Bu)or —(CH₂)₄NH₂.

In a second aspect, the present invention includes compounds of Formula(I), within the scope of the first aspect wherein:

L is —C(O)NR¹⁰—, —NR¹⁰C(O)—, —CH₂CONR¹⁰—, or —NR¹⁰COCH₂—;

R³ is —(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(r)C(O)NR⁸(CH₂)_(s)CO₂R^(3b),—(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)-phenyl substituted with 0-3 R^(3a) and0-1 R^(3d), —(CH₂)_(r)-naphthyl substituted with 0-3 R^(3a) and 0-1R^(3d), —(CH₂)_(r)-indanyl substituted with 0-3 R^(3a) and 0-1 R^(3d),or —(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(3a) and 0-1 R^(3d);

R⁴ is H, F, Cl, Br, I, OCF₃, CF₃, OR^(a), SR^(a), CN, NO₂, —C(O)R^(a),—C(O)OR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with0-2 R^(4a), C₂₋₆ alkenyl substituted with 0-2 R^(4a), C₂₋₆ alkynylsubstituted with 0-2 R^(4a), phenyl substituted with 0-2 R^(4b), or a5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(4b);

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-2 R^(10a), —(CH₂)_(r)-phenyl substituted with 0-2 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(d); and

R¹¹ is C₁₋₄ haloalkyl, —(CH₂)_(r)—CONR⁸R⁹, C₁₋₆ alkyl substituted with0-2 R^(11a), C₂₋₆ alkenyl substituted with 0-2 R^(11a), C₂₋₆ alkynylsubstituted with 0-2 R^(11a), —(CH₂)—C₃₋₁₀ carbocycle substituted with0-3 R^(11b), or —(CH₂)_(r)-5- to 10-membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(11b).

In a third aspect, the present invention includes compounds of Formula(I), within the scope of the first aspect wherein:

R¹ is, independently at each occurrence, F, Cl, Me, Et, —NH₂,—C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂NHCO₂Bn, —CH₂NHCO₂(t-Bu),—CH(Me)NH₂, —C(Me)₂NH₂, —NHEt, —NHCO₂(t-Bu), —NHCO₂Bn, —SO₂NH₂, OR^(a),or —CH₂R^(1a);

R³ is —CO₂H, —CO₂Me, —C(O)NHCH₂CO₂H, —C(O)NHCH₂CO₂Et, —C(O)NH₂,—C(O)NHMe, —C(O)NHBn, —(CH₂)_(r)-phenyl substituted with 0-2 R^(3a) and0-1 R^(3d), naphthyl substituted with 0-2 R^(3a) and 0-1 R^(3d), indanylsubstituted with 0-2 R^(3a) and 0-1 R^(3d), or —(CH₂)_(r)5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(3a) and 0-1 R^(3d);

R⁴ is H, F, Cl, Br, CF₃, OMe, NH₂, CO₂H, CO₂Me, CO₂Et, —CONR⁸R⁹, C₁₋₆alkyl substituted with 0-2 R^(4a), phenyl substituted with 0-2 R^(4b),or a 5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(4b);

R¹⁰ is, independently at each occurrence, H, Me, benzyl, phenethyl,—CH₂CH₂CO₂H, —CH₂CH₂CO₂Me, —CH₂CH₂CO₂Et, —CH₂CH₂CONH₂, or—CH₂CH₂CONHCH₂CH₂Ph; and

R¹¹ is C₁₋₆ alkyl, —CH₂CONR⁸R⁹, —CH₂CH₂CONR⁸R⁹, —CH₂OBn, —CH₂SBn,—(CH₂)_(r)—C₃₋₇ cycloalkyl substituted with 0-2 R^(11b),—(CH₂)_(r)-phenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-naphthylsubstituted with 0-2 R^(11b), or —(CH₂)_(r)-5-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-2 R^(11b).

In a fourth aspect, the present invention includes a compound of Formula(II):

or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the first aspectwherein:

A is substituted with 0-1 R¹ and 0-2 R² and selected from: C₃₋₇cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, pyridyl,indazolyl, benzimidazolyl, benzisoxazolyl, isoquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,quinazolinyl, 1H-quinazolin-4-onyl, 2H-isoquinolin-1-onyl,3H-quinazolin-4-onyl, 3,4-dihydro-2H-isoquinolin-1-onyl,2,3-dihydroisoindolinonyl, and phthalazinyl;

L is —C(O)NH— or —NHC(O)—;

R¹ is, independently at each occurrence, F, Cl, Me, Et, —NH₂,—C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, —CH₂NHCO₂Bn, —CH₂NHCO₂(t-Bu), —CH(Me)NH₂,—CMe₂NH₂, —NHEt, —NHCO₂(t-Bu), —NHCO₂Bn, —SO₂NH₂, OR^(a), or —CH₂R^(1a);

R² is, independently at each occurrence, ═O, F, Cl, Me, OMe, OEt, Bn,—CH₂OMe, —CH₂OEt, —CH₂OPh, or —(CH₂)₂Ph;

R³ is —CO₂H, —CO₂Me, —C(O)NHCH₂CO₂H, —C(O)NHCH₂CO₂Et, —C(O)NH₂,—C(O)NHMe, —C(O)NHBn, phenyl substituted with 0-2 R^(3a), naphthylsubstituted with 0-2 R^(3a), indanyl substituted with 0-2 R^(3a), or a5- to 10-membered heterocycle comprising: carbon atoms and 1-2heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(3a);

R⁴ is H, F, Cl, Br, OMe, NH₂, CF₃, CO₂H, CO₂Me, CO₂Et, C₁₋₆ alkylsubstituted with 0-2 R^(4a), phenyl substituted with 0-2 R^(4b), or 5-10membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(4b));

R¹¹ is C₁₋₆ alkyl, —CH₂CONR⁸R⁹, —CH₂CH₂CONR⁸R⁹, —CH₂OBn, —CH₂SBn,—(CH₂)_(r)—C₃₋₇ cycloalkyl substituted with 0-2 R^(11b),—(CH₂)_(r)-phenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-naphthylsubstituted with 0-2 R^(11b), or —(CH₂)_(r)-5- to 10-membered heteroarylsubstituted with 0-2 R^(11b) and selected from thiazolyl, oxazolyl,triazolyl, tetrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, and tetrahydroisoquinolinyl; and

R^(11b) is, independently at each occurrence, H, F, Cl, Br, CF₃, OMe,OEt, O(i-Pr), OCF₃, OCHF₂, CN, OPh, OBn, NO₂, —NH₂, —C(O)R^(a),—C(O)OR^(a), —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —NR⁸C(O)₂R^(c), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —SO₂R^(c), C₁-C₄-alkyl, Ph, or Bn;

alternately, when two R^(11b) groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-2R^(g).

In a fifth aspect, the present invention includes a compound of Formula(II):

or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the first aspectwherein:

A is 4-CH₂NH₂-cyclohexyl, 4-CO₂Me-cyclohexyl, 4-CONH₂-cyclohexyl,4-NHCO₂(t-Bu)-cyclohexyl, 4-NHCO₂Bn-cyclohexyl, phenyl, 4-Me-phenyl,3-OMe-phenyl, 4-CH₂NH₂-phenyl, 3-CONH₂-phenyl, 4-CONH₂-phenyl,3-amidino-phenyl, 4-amidino-phenyl, 2-F-4-Me-phenyl,2-Bn-4-CH₂NH₂-phenyl, 4-SO₂NH₂-phenyl, 2-F-5-OMe-phenyl,2-F-4-Cl-phenyl, 2-F-4-CH₂NH₂-phenyl, 2-F-4-CONH₂-phenyl,2-Cl-4-CONH₂-phenyl, 2-Et-4-CH₂NH₂-phenyl, 2-NHEt-4-CH₂NH₂-phenyl,2-OMe-4-CONH₂-phenyl, 3-OMe-4-CONH₂-phenyl,1,2,3,4-tetrahydronaphth-2-yl, 3-Cl-thien-2-yl, indol-5-yl, indol-6-yl,indazol-6-yl, 3-NH₂-indazol-6-yl, 3-NH₂-indazol-5-yl,1-Me-3-NH₂-indazol-6-yl, 3-NH₂-benzisoxazol-6-yl,1,2,3,4-tetrahydroisoquinolin-6-yl, 1,2,3,4-tetrahydroisoquinolin-3-yl,2-COPh-1,2,3,4-tetrahydroisoquinolin-3-yl,2-CO₂Bn-1,2,3,4-tetrahydroisoquinolin-3-yl,1,2,3,4-tetrahydroisoquinolin-1-on-6-yl, 2H-isoquinolin-1-on-6-yl,isoquinolin-6-yl, 1-NH₂-isoquinolin-6-yl, 1-NH₂-3-Me-isoquinolin-6-yl,1-NH₂-5,6,7,8-tetrahydroisoquinolin-6-yl, 4-NH₂-quinazolin-7-yl,3H-quinazolin-4-on-7-yl,

R³ is CO₂H, CO₂Me, —C(O)NHCH₂CO₂H, —C(O)NHCH₂CO₂Et, —C(O)NH₂, —C(O)NHMe,—C(O)NHBn, phenyl, phenethyl, —(CH═CH)-phenyl, 3-biphenyl, 4-biphenyl,3,4-methylenedioxyphenyl, 1-naphthyl, 2-naphthyl, 3-NH₂-phenyl,3-NMe₂-phenyl, 4-OPh-phenyl, 4-OBn-phenyl, 4-(t-butoxymethyl)-phenyl,4-SO₂Me-phenyl, 3-CN-phenyl, 4-CN-phenyl, 3-F-phenyl, 4-F-phenyl,3-Cl-phenyl, 4-Cl-phenyl, 3-Br-phenyl, 4-Br-phenyl, 3-OH-phenyl,4-OH-phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 4-OMe-phenyl, 3-CF₃-phenyl,4-CF₃-phenyl, 3-CO₂H-phenyl, 4-CO₂H-phenyl, 3-CO₂Me-phenyl,4-CO₂Me-phenyl, 3-CH₂CO₂H-phenyl, 4-CH₂CO₂H-phenyl, 4-CH₂CO₂Me-phenyl,3-CH₂CO₂Et-phenyl, 4-CH₂CO₂Et-phenyl, 3-CONH₂-phenyl, 4-CONH₂-phenyl,3-CH₂CONH₂-phenyl, 4-CH₂CONH₂-phenyl, 4-CONHMe-phenyl, 4-CONMe₂-phenyl,4-amidino-phenyl, 3-NHCOMe-phenyl, 4-NHCOMe-phenyl, 4-NHCO₂Me-phenyl,4-SO₂NH₂-phenyl, 3-NHSO₂Me-phenyl, 4-NHSO₂Me-phenyl, 2,4-diF-phenyl,3-F-4-CN-phenyl, 3-CN-5-F-phenyl, 3-F-4-CONH₂-phenyl,3-CO₂H-4-CN-phenyl, 3-NMe₂-4-CN-phenyl, 3-Ph-4-CONH₂-phenyl,4-(2-oxo-1-piperidino)-phenyl, thiazol-2-yl, 4-CO₂Me-thiazol-2-yl,4-CONH₂-thiazol-2-yl, 1-Bn-pyazol-4-yl, 5-Ph-oxazol-2-yl,5-CONH₂-thien-2-yl, 5-CO₂H-thien-2-yl, pyrid-2-yl, pyrid-3-yl,pyrid-4-yl, 6-NH₂-pyrid-3-yl, benzimidazol-2-yl, 1-Me-benzimidazol-2-yl,benzoxazol-2-yl, benzothiazol-2-yl, 3-NH₂-benzisoxazol-6-yl,3-NH₂-benzisoxazol-5-yl, indazol-5-yl, indazol-6-yl, 3-NH₂-indazol-5-yl,3-OH-indazol-5-yl, 3-NH₂-indazol-6-yl, 3-NH₂-4-F-indazol-6-yl,3-NH₂-5-F-indazol-6-yl, 3-NH₂-7-F-indazol-6-yl,4-imino-3,4-dihydro-2H-phthalazin-1-on-7-yl, 3-(5-tetrazolyl)-phenyl,2,3-dihydro-isoindol-1-on-6-yl, quinolin-5-yl, quinolin-6-yl,quinolin-8-yl, isoquinolin-5-yl, 2H-isoquinolin-1-on-6-yl,2,4-diaminoquinazolin-7-yl, or 4-NH₂-quinazolin-7-yl;

R⁴ is H, Me, Br, Cl, CF₃, CO₂H, CO₂Me, CO₂Et, phenyl, 3-F-4-CN-phenyl,or 3-NH₂-6-indazolyl; and

R¹¹ is Me, neopentyl, cyclohexylmethyl, —CH₂CH₂CONHBn,—CH₂CH₂CONH(CH₂CH₂Ph), —CH₂CH₂CON(Me)Bn, benzyl, phenethyl, 2-Me-benzyl,3-Me-benzyl, 4-Me-benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl,2-Cl-benzyl, 3-Cl-benzyl, 4-Cl-benzyl, 2-Br-benzyl, 3-Br-benzyl,4-Br-benzyl, 3-CF₃-benzyl, 4-CF₃-benzyl, 2-NH₂-benzyl, 3-NH₂-benzyl,2-NO₂-benzyl, 3-NO₂-benzyl, 4-NO₂-benzyl, 3-OMe-benzyl, 4-OMe-benzyl,3-OCF₂H-benzyl, 2-OCF₃-benzyl, 3-OCF₃-benzyl, 2-OPh-benzyl,3-OPh-benzyl, 2-OBn-benzyl, 3-OBn-benzyl, 4-OBn-benzyl, 4-COPh-benzyl,3-CO₂H-benzyl, 3-CO₂Me-benzyl, 3-NHAc-benzyl, 2-NHCOPh-benzyl,2-NHCOBn-benzyl, 3-NHCOBn-benzyl, 3-N(Me)COPh-benzyl,3-(-NHCOCH₂CH₂Ph)-benzyl, 2-NHSO₂Ph-benzyl, 3-NHSO₂Ph-benzyl,3-[SO₂N(Me)Ph]-benzyl, 3-[N(Me)SO₂Ph]-benzyl, 3-[CONH(i-Bu)]-benzyl,3-[CONH(t-Bu)]-benzyl, 3-[CONH(isopentyl)]-benzyl,3-[CONH(2-Me-Ph)]-benzyl, 3-[CONH(3-Me-Ph)]-benzyl,3-[CONH(4-Me-Ph)]-benzyl, 3-[CONH(4-F-Ph)]-benzyl,3-[CONH(1-naphthyl)]-benzyl, 3-(CONHBn)-benzyl,3-[CONH(4-Cl-Bn)]-benzyl, 3-[CONH(4-OMe-Bn)]-benzyl,3-[CONHCH₂CH₂Ph]-benzyl, 3-[CONHCH₂CH₂(4-OMe-Ph)]-benzyl,3-[CONHCH₂CH₂(2-Cl-Ph)]-benzyl, 3-[CONHCH₂CH₂(3-Cl-Ph)]-benzyl,3-[CONHCH₂CH₂(4-Cl-Ph)]-benzyl, 3-[CONH(CH₂)₃Ph]-benzyl,3-[CONMe₂]-benzyl, 3-[CON(Me)(Et)]-benzyl, 3-[CON(Me)(i-Pr)]-benzyl,3-[CON(Me)(i-Bu)]-benzyl, 3-[CON(Me)Ph]-benzyl,3-[CON(Me)(3-Me-Ph)]-benzyl, 3-[CON(Me)(4-Me-Ph)]-benzyl,3-[CON(Me)Bn]-benzyl, 3-[CON(Me)(3-Cl-Bn)]-benzyl,3-[CON(Me)(4-Cl-Bn)]-benzyl, 3-[CON(Me)(CH₂CH₂Ph)]-benzyl,3-[CON(Et)Ph]-benzyl, 3-[CO(1-piperidino)]-benzyl,3-[CO(4-Ph-1-piperidino)]-benzyl,3-[CO(1,2,3,4-tetrahydroisoquinolino)]-benzyl, 2-Ph-benzyl, 3-Ph-benzyl,4-Ph-benzyl, 3-phenethyl-benzyl, —CH₂OBn, —CH₂SBn, 1-naphthylmethyl,2-naphthylmethyl, thiazol-4-ylmethyl, pyrid-2-ylmethyl,pyrid-3-ylmethyl, pyrid-4-ylmethyl, 1-Bn-imidazol-4-ylmethyl,benzothiazol-2-ylmethyl,

In a sixth aspect, the present invention includes a compound of Formula(II):

or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the first aspectwherein:

R³ is 3-NH₂-indazol-5-yl, 3-OH-indazol-5-yl, 3-NH₂-benzisoxazol-6-yl,3-NH₂-benzisoxazol-5-yl, indazol-5-yl, indazol-6-yl, 3-NH₂-indazol-6-yl,3-NH₂-4-F-indazol-6-yl, 3-NH₂-5-F-indazol-6-yl, 3-NH₂-7-F-indazol-6-yl,isoquinolin-5-yl, quinolin-5-yl, quinolin-8-yl,2H-isoquinolin-1-on-6-yl, 2,4-diaminoquinazolin-7-yl, or4-NH₂-quinazolin-7-yl.

In a seventh aspect, the present invention includes compounds of Formula(Ha) within the scope of the sixth aspect wherein:

L is —C(O)NR¹⁰— or —NR¹⁰C(O)—;

R¹ is, independently at each occurrence, F, Cl, Me, Et, —NH₂,—C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂NHCO₂Bn, —CH₂NHCO₂(t-Bu),—CH(Me)NH₂, —C(Me)₂NH₂, —NHEt, —NHCO₂(t-Bu), —NHCO₂Bn, —SO₂NH₂, OR^(a),or —CH₂R^(1a);

R⁴ is H, F, Cl, Br, OMe, NH₂, CF₃, CO₂H, CO₂Me, CO₂Et, —CONR⁸R⁹, C₁₋₆alkyl substituted with 0-2 R^(4a), phenyl substituted with 0-2 R^(4b),or a 5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(4b);

R¹⁰ is, independently at each occurrence, H, Me, benzyl, phenethyl,—CH₂CH₂CO₂H, —CH₂CH₂CO₂Me, —CH₂CH₂CO₂Et, —CH₂CH₂CONH₂, or—CH₂CH₂CONHCH₂CH₂Ph;

R¹¹ is C₁-C₆ alkyl, —CH₂CONR⁸R⁹, —CH₂CH₂CONR⁸R⁹, —CH₂OBn, —CH₂SBn,—(CH₂)_(r)—C₃₋₇ cycloalkyl substituted with 0-2 R^(11b),—(CH₂)_(r)-phenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-naphthylsubstituted with 0-2 R^(11b), or —(CH₂)_(r)-5-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-2 R^(11b); and

R^(11b) is, independently at each occurrence, H, F, Cl, Br, CF₃, OMe,OEt, O(i-Pr), OCF₃, OCHF₂, CN, OPh, OBn, NO₂, —NH₂, —C(O)R^(a),—C(O)OR^(a), —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —N⁸CO₂R^(c), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —SO₂R^(c), C₁-C₄-alkyl, Ph, or Bn.

In an eighth aspect, the present invention includes compounds of Formula(II), within the scope of the seventh aspect wherein:

A is substituted with 0-1 R¹ and 0-2 R² and selected from: C₃₋₇cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, pyridyl,indazolyl, benzimidazolyl, benzisoxazolyl, isoquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,quinazolinyl, 1H-quinazolin-4-onyl, 2H-isoquinolin-1-onyl,3H-quinazolin-4-onyl, 3,4-dihydro-2H-isoquinolin-1-onyl,2,3-dihydroisoindolinonyl, and phthalazinyl; and

R¹⁰ is H.

In a ninth aspect, the present invention includes compounds of Formula(II), within the scope of the eighth aspect wherein:

A is 4-CH₂NH₂-cyclohexyl, 4-CO₂Me-cyclohexyl, 4-CONH₂-cyclohexyl,4-NHCO₂(t-Bu)-cyclohexyl, 4-NHCO₂Bn-cyclohexyl, phenyl, 4-Me-phenyl,3-OMe-phenyl, 4-CH₂NH₂-phenyl, 3-CONH₂-phenyl, 4-CONH₂-phenyl,3-amidino-phenyl, 4-amidino-phenyl, 2-F-4-Me-phenyl,2-Bn-4-CH₂NH₂-phenyl, 4-SO₂NH₂-phenyl, 2-F-5-OMe-phenyl,2-F-4-Cl-phenyl, 2-F-4-CH₂NH₂-phenyl, 2-F-4-CONH₂-phenyl,2-Cl-4-CONH₂-phenyl, 2-Et-4-CH₂NH₂-phenyl, 2-NHEt-4-CH₂NH₂-phenyl,2-OMe-4-CONH₂-phenyl, 3-OMe-4-CONH₂-phenyl,1,2,3,4-tetrahydronaphth-2-yl, 3-Cl-thien-2-yl, indol-5-yl, indol-5-yl,indazol-5-yl, indazol-6-yl, 3-NH₂-indazol-6-yl, 3-NH₂-indazol-5-yl,1-Me-3-NH₂-indazol-6-yl, 3-NH₂-benzisoxazol-6-yl,1,2,3,4-tetrahydroisoquinolin-6-yl, 1,2,3,4-tetrahydroisoquinolin-3-yl,2-COPh-1,2,3,4-tetrahydroisoquinolin-3-yl,2-CO₂Bn-1,2,3,4-tetrahydroisoquinolin-3-yl,1,2,3,4-tetrahydroisoquinolin-1-on-6-yl, 2H-isoquinolin-1-on-6-yl,isoquinolin-6-yl, 1-NH₂-isoquinolin-6-yl, 1-NH₂-3-Me-isoquinolin-6-yl,1-NH₂-5,6,7,8-tetrahydroisoquinolin-6-yl, 4-NH₂-quinazolin-7-yl,3H-quinazolin-4-on-7-yl,

R⁴ is H, Me, Br, Cl, CF₃, CO₂H, CO₂Me, CO₂Et, phenyl, 3-F-4-CN-phenyl,or 3-NH₂-6-indazolyl; and

R¹¹ is Me, neopentyl, cyclohexylmethyl, —CH₂CH₂CONHBn,—CH₂CH₂CONH(CH₂CH₂Ph), —CH₂CH₂CON(Me)Bn, benzyl, phenethyl, 2-Me-benzyl,3-Me-benzyl, 4-Me-benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl,2-Cl-benzyl, 3-Cl-benzyl, 4-Cl-benzyl, 2-Br-benzyl, 3-Br-benzyl,4-Br-benzyl, 3-CF₃-benzyl, 4-CF₃-benzyl, 2-NH₂-benzyl, 3-NH₂-benzyl,2-NO₂-benzyl, 3-NO₂-benzyl, 4-NO₂-benzyl, 3-OMe-benzyl, 4-OMe-benzyl,3-OCF₂H-benzyl, 2-OCF₃-benzyl, 3-OCF₃-benzyl, 2-OPh-benzyl,3-OPh-benzyl, 2-OBn-benzyl, 3-OBn-benzyl, 4-OBn-benzyl, 4-COPh-benzyl,3-CO₂H-benzyl, 3-CO₂Me-benzyl, 3-NHAc-benzyl, 2-NHCOPh-benzyl,2-NHCOBn-benzyl, 3-NHCOBn-benzyl, 3-N(Me)COPh-benzyl,3-(-NHCOCH₂CH₂Ph)-benzyl, 2-NHSO₂Ph-benzyl, 3-NHSO₂Ph-benzyl,3-[SO₂N(Me)Ph]-benzyl, 3-[N(Me)SO₂Ph]-benzyl, 3-[CONH(i-Bu)]-benzyl,3-[CONH(t-Bu)]-benzyl, 3-[CONH(isopentyl)]-benzyl,3-[CONH(2-Me-Ph)]-benzyl, 3-[CONH(3-Me-Ph)]-benzyl,3-[CONH(4-Me-Ph)]-benzyl, 3-[CONH(4-F-Ph)]-benzyl,3-[CONH(1-naphthyl)]-benzyl, 3-(CONHBn)-benzyl,3-[CONH(4-Cl-Bn)]-benzyl, 3-[CONH(4-OMe-Bn)]-benzyl,3-[CONHCH₂CH₂Ph]-benzyl, 3-[CONHCH₂CH₂(4-OMe-Ph)]-benzyl,3-[CONHCH₂CH₂(2-Cl-Ph)]-benzyl, 3-[CONHCH₂CH₂(3-Cl-Ph)]-benzyl,3-[CONHCH₂CH₂(4-Cl-Ph)]-benzyl, 3-[CONH(CH₂)₃Ph]-benzyl,3-[CONMe₂]-benzyl, 3-[CON(Me)(Et)]-benzyl, 3-[CON(Me)(i-Pr)]-benzyl,3-[CON(Me)(i-Bu)]-benzyl, 3-[CON(Me)Ph]-benzyl,3-[CON(Me)(3-Me-Ph)]-benzyl, 3-[CON(Me)(4-Me-Ph)]-benzyl,3-[CON(Me)Bn]-benzyl, 3-[CON(Me)(3-Cl-Bn)]-benzyl,3-[CON(Me)(4-Cl-Bn)]-benzyl, 3-[CON(Me)(CH₂CH₂Ph)]-benzyl,3-[CON(t)Ph]-benzyl, 3-[CO(1-piperidino)]-benzyl,3-[CO(4-Ph-1-piperidino)]-benzyl,3-[CO(1,2,3,4-tetrahydroisoquinolino)]-benzyl, 2-Ph-benzyl, 3-Ph-benzyl,4-Ph-benzyl, 3-phenethyl-benzyl, —CH₂OBn, —CH₂SBn, 1-naphthylmethyl,2-naphthylmethyl, thiazol-4-ylmethyl, pyrid-2-ylmethyl,pyrid-3-ylmethyl, pyrid-4-ylmethyl, 1-Bn-imidazol-4-ylmethyl,benzothiazol-2-ylmethyl,

In a tenth aspect, the present invention includes compounds of Formula(II), within the scope of the eighth aspect wherein:

A is 4-CH₂NH₂-cyclohexyl, 4-NHCO₂(t-Bu)-cyclohexyl,4-NHCO₂Bn-cyclohexyl, or 1-NH₂-5,6,7,8-tetrahydroisoquinolin-6-yl;

L is —C(O)NH— or NHC(O)—;

R³ is indazol-5-yl, indazol-6-yl, 3-NH₂-indazol-5-yl, 3-OH-indazol-5-yl,3-NH₂-indazol-6-yl, 3-NH₂-4-F-indazol-6-yl, 3-NH₂-5-F-indazol-6-yl,3-NH₂-7-F-indazol-6-yl, or 4-NH₂-quinazolin-7-yl;

R⁴ is H, Me, F, Br, Cl, or CF₃; and

R¹¹ is benzyl substituted with 0-2 R^(11b).

In an eleventh aspect, the present invention includes compounds ofFormula (II), within the scope of the tenth aspect wherein:

A is 4-CH₂NH₂-cyclohexyl;

L is —C(O)NH—; and

R³ is 3-NH₂-indazol-6-yl or 4-NH₂-quinazolin-7-yl.

In a twelfth aspect, the present invention includes a compound ofFormula (II):

or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the first aspectwherein:

A is substituted with 0-2 R¹ and 0-1 R² and selected from: C₃₋₇cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, pyridyl,indazolyl, benzimidazolyl, benzisoxazolyl, isoquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,quinazolinyl, 1H-quinazolin-4-onyl, 2H-isoquinolin-1-onyl,3H-quinazolin-4-onyl, 3,4-dihydro-2H-isoquinolin-1-onyl,2,3-dihydroisoindolinonyl, and phthalazinyl;

L is —C(O)NR¹⁰— or —NR¹⁰C(O)—;

R³ is —(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atomsand 1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(3a) and 0-1 R^(3d);

R⁴ is H, F, Cl, Br, OMe, NH₂, CF₃, CO₂H, CO₂Me, CO₂Et, —CONR⁸R⁹, C₁₋₆alkyl substituted with 0-2 R^(4a), phenyl substituted with 0-2 R^(4b),or a 5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(4b); and

R¹¹ is benzyl substituted with 0-2 R^(11b).

In another aspect, the present invention includes a compound of Formula(II), within the scope of the twelfth aspect wherein:

R³ is —(CH₂)_(r)-9- to 10-membered bicyclic heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(3a).

In a thirteenth aspect, the present invention includes a compound ofFormula (II):

or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the first aspectwherein:

A is substituted with 0-1 R¹ and 0-2 R² and selected from: C₃₋₇cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, pyridyl,indazolyl, benzimidazolyl, benzisoxazolyl, isoquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,quinazolinyl, 1H-quinazolin-4-onyl, 2H-isoquinolin-1-onyl,3H-quinazolin-4-onyl, 3,4-dihydro-2H-isoquinolin-1-onyl,2,3-dihydroisoindolinonyl, and phthalazinyl;

L is —C(O)NR¹⁰— or —NR¹⁰C(O)—;

R³ is —(CH₂)_(r)-phenyl substituted with 0-3 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-naphthyl substituted with 0-3 R^(3a) and 0-1 R^(3d), or—(CH₂)_(r)-indanyl substituted with 0-3 R^(3a) and 0-1 R^(3d);

R⁴ is, independently at each occurrence, H, Me, Br, Cl, CF₃, CO₂H,CO₂Me, CO₂Et, phenyl, 3-F-4-CN-phenyl, or 3-NH₂-6-indazolyl; and

R¹¹ is benzyl substituted with 0-2 R^(11b).

In another aspect, the present invention includes a compound of Formula(II), within the scope of the thirteenth aspect wherein:

R³ is —(CH₂)_(r)-phenyl substituted with 0-3 R^(3a).

In a fourteenth aspect, the present invention includes a compound ofFormula

or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the first aspectwherein:

R^(3a) is, independently at each occurrence, ═O, F, Cl, Br, Me, CN, OH,NH₂, OMe, O(t-Bu), OBn, CF₃, CO₂H, CO₂Me, —CH₂CO₂H, —CH₂CO₂Me,—CH₂CO₂Et, —NHCOMe, —CONH₂, —CH₂CONH₂, —CONHMe, —CONMe₂, —C(═NH)NH₂,—NR⁷R⁸, —SO₂Me, —SO₂NH₂, Ph, or 2-oxo-piperidin-1-yl;

R^(3d) is H or C₁₋₄ alkyl;

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-2 R^(10a), —(CH₂)_(r)-phenyl substituted with 0-2 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(d); and

R¹¹ is C₁₋₄ haloalkyl, —(CH₂)_(r)—CONR⁸R⁹, C₁₋₆ alkyl substituted with0-2 R^(11a), C₂₋₆ alkenyl substituted with 0-2 R^(11a), C₂₋₆ alkynylsubstituted with 0-2 R^(11a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(11b), or —(CH₂)_(r)-5-10 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(11b).

In a fifteenth aspect, the present invention includes compounds ofFormula (III), within the scope of the fourteenth aspect wherein:

R¹ is, independently at each occurrence, —NH₂, —C(═NH)NH₂, —C(O)NH₂,—CH₂NH₂, —CH(Me)NH₂, —C(Me)₂NH₂, or —CH₂CH₂NH₂;

R¹⁰ is H, Me, benzyl, or phenethyl; and

R¹¹ is Me, —(CH₂)_(r)-phenyl substituted with 0-1 R^(11b), or—(CH₂)_(r)-5-10 membered heteroaryl comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-1 R^(11b).

In a sixteenth aspect, the present invention includes a compound ofFormula (IV):

or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the first aspectwherein:

A is cyclohexyl substituted with 1 R¹, phenyl substituted with 1 R¹,pyridyl substituted with 1 R¹, naphthyl substituted with 1 R¹,benzisoxazole substituted with 1 R¹, or isoquinolinyl substituted with0-1 R¹;

L is —C(O)NH—, —C(O)NMe-, —C(O)N(benzyl)-, —C(O)N(phenethyl)-, —NHC(O)—,—CH₂C(O)NH—, —NHC(O)CH₂—, —C(O)NHCH₂—, or —NHC(O)CH₂—;

R¹ is, independently at each occurrence, —NH₂, —C(═NH)NH₂, —C(O)NH₂, or—CH₂NH₂;

R^(3a) is F, Cl, Br, Me, CN, OMe, CF₃, CO₂H, CO₂Me, CO₂Et, —CH₂CO₂H,—CH₂CO₂Me, —CH₂CO₂Et, CONH₂, —CONHMe, —CON(Me)₂, —CH₂CONH₂, or—C(═NH)NH₂;

R⁶ is H;

R¹⁰ is H, Me, benzyl, or phenethyl; and

R¹¹ is Me, —(CH₂)_(r)-phenyl substituted with 0-1 R^(11b) or—(CH₂)_(r)-5-10 membered heteroaryl substituted with 0-1 R^(11b) andselected from thiazolyl, imidazolyl, pyridyl, and benzothiazolyl.

In a seventeenth aspect, the present invention includes compounds ofFormula (IV), within the scope of the sixteenth aspect wherein:

A is 4-CH₂NH₂-cyclohexyl or 4-amidino-phenyl; and

R^(3a) is, independently at each occurrence, CO₂H, CO₂Me, —CH₂CO₂H,—CH₂CO₂Et, —CONH₂, or —CH₂CONH₂.

In an eighteenth aspect, the present invention provides, inter alia, acompound of Formula (V):

or its stereoisomers, tautomers, a pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

A is C₃₋₁₀ carbocycle substituted with 0-1 R¹ and 0-3 R², or a 5- to12-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-1 R¹ and 0-3 R²; provided when A is a heterocyclecontaining one or more nitrogen atoms, A is not attached to L via any ofthe nitrogen atoms on the A ring;

X¹, X², and X³ are independently CR³, CR⁴, CR⁴R⁵, O, S(O)_(p), N, NR³,NR⁶, or C(O); provided that no S—S, S—O, or O—O bond is present in thering;

provided that

is other than

Z is —C(R¹¹)(R¹²)—, —C(R¹¹)(R¹²)—(CH₂)—, —NR¹³—, or —NR¹³CH₂—;

L is —C(O)NR¹⁰—, —NR¹⁰C(O)—, —CH₂C(O)NR¹⁰—, —CH₂NR¹⁰C(O)—,—C(O)NR¹⁰CH₂—, —NR¹⁰C(O)CH₂—, —S(O)₂NR¹⁰—, —NR¹⁰S(O)₂—, —CH₂S(O)₂NR¹⁰—,—CH₂NR¹⁰S(O)₂—, —S(O)₂NR¹⁰CH₂—, —NR¹⁰S(O)₂CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂NR⁷—, —NR⁷CH₂—, —CH₂CH₂NR⁷—, —NR⁷CH₂CH₂, —CH₂NR⁷CH₂—, —CH₂O—,—OCH₂—, —CH₂S(O)_(p)—, —S(O)pCH₂—, —CH₂CH₂O—, —OCH₂CH₂—, —CH₂OCH₂—,—CH₂CH₂S(O)_(p)—, —S(O)_(p)CH₂CH₂—, —CH₂S(O)_(p)CH₂—, —CH₂C(O),—CH₂C(O)CH₂—, —CH₂CH₂C(O)—, —C(O)CH₂CH₂—, or —C(O)CH₂—;

R¹ is, independently at each occurrence, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃alkyl)₂, —C(═NH)NH₂, —C(O)NR⁸R⁹, —S(O)_(p)NR⁸R⁹, —(CH₂)_(r)NR⁷R⁸,—(CH₂)_(r)NR⁷C(O)OR^(a), —CH₂NH₂, —CH₂NH(C₁₋₃ alkyl), —CH₂N(C₁₋₃alkyl)₂, —CH₂CH₂NH₂, —CH₂CH₂NH(C₁₋₃ alkyl), —CH₂CH₂N(C₁₋₃ alkyl)₂,—CH(C₁₋₄ alkyl)NH₂, —C(C₁₋₄ alkyl)₂NH₂, —C(═NR^(8a))NR⁷R⁸,—NHC(═NR^(8a))NR⁷R⁸, ═NR⁸, —NR⁸CR⁸(═NR^(8a)), F, Cl, Br, I, OCF₃, CF₃,—(CH₂)_(r)OR^(a), —(CH₂)_(r)SR^(a), CN, 1-NH₂-1-cyclopropyl, or C₁₋₆alkyl substituted with 0-1 R^(1a);

R^(1a) is H, —C(═NR^(8a))NR⁷R⁸, —NHC(═NR^(8a))NR⁷R⁸, —NR⁸CH(═NR^(8a)),—NR⁷R⁸, —C(O)NR⁸R⁹, F, OCF₃, CF₃, OR^(a), SR^(a), CN, —NR⁹SO₂NR⁸R⁹,—NR⁸SO₂R^(c), —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, or —(CF₂)_(r)CF₃;

R² is, independently at each occurrence, H, ═O, F, Cl, Br, I, OCF₃, CF₃,CHF₂, CN, NO₂, OR^(a), SR^(a), —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —S(O)₂NR⁸R⁹, —NR⁸S(O)₂R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(2a), C₂₋₆alkenyl substituted with 0-2 R^(2a), C₂₋₆ alkynyl substituted with 0-2R^(2a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(2b), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(2b);

R^(2a) is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸,CN, OCF₃, CF₃, OR^(a), SR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸SO₂R^(c), —S(O)R^(c), or —S(O)₂R^(c);

R^(2b) is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸,CN, NO₂, OR^(a), SR^(a), —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸,—C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —S(O)₂NR⁸R⁹, —S(O)₂R^(c), —NR⁸SO₂NR⁸R⁹,—NR⁸SO₂R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄ haloalkoxy;

alternately, when R¹ and R² groups are substituted on adjacent ringatoms, they can be taken together with the ring atoms to which they areattached to form a 5- to 7-membered carbocycle or heterocyclecomprising: carbon atoms and 0-4 heteroatoms selected from N, O, andS(O)_(p), wherein said carbocycle or heterocycle is substituted with 0-2R^(2b);

R³ is, independently at each occurrence, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)C(O)NR⁸(CH₂)_(s)CO₂R^(3b), —(CH₂)_(r)CO₂R^(3b),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(3a) and 0-1 R^(3d),or —(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(3a) and 0-1 R^(3d);

R^(3a) is, independently at each occurrence, ═O, F, Cl, Br, I, OCF₃,CF₃, NO₂, CN, —(CH₂)_(r)OR^(3b), —(CH₂)_(r)SR^(3b), —(CH₂)_(r)NR⁷R⁸,C(═NR^(8a))NR⁸R⁹, —NHC(═NR^(8a))NR⁷R⁸, —NR⁸CR⁸(═NR^(8a)),—(CH₂)_(r)NR⁸C(O)R^(3b), ═NR⁸, —(CH₂)_(r)NR⁸C(O)R^(3b),—(CH₂)_(r)NR⁸C(O)₂R^(3b), —(CH₂)_(r)S(O)_(p)NR⁸R⁹,—(CH₂)_(r)NR⁸S(O)_(p)R^(3c), —S(O)_(p)R^(3c), —S(O)_(p)R^(3c),—C(O)—C₁₋₄ alkyl, —(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)OC(O)NR⁸R⁹, —NHCOCF₃, —NHSO₂CF₃, —SO₂NHR^(3b), —SO₂NHCOR^(3c),—SO₂NHCO₂R^(3c), —CONHSO₂R^(3c), —NHSO₂R^(3c), —CONHOR^(3b), C₁₋₄haloalkyl, C₁₋₄ haloalkoxy-, C₁₋₆ alkyl substituted by R^(3d), C₂₋₆alkenyl substituted by R^(3d), C₂₋₆ alkynyl substituted by R^(3d), C₃₋₆cycloalkyl substituted by 0-1 R^(3d), —(CH₂)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(3d);

alternately, when two R^(3a) groups are located on adjacent atoms, theycan be taken together with the atoms to which they are attached to forma C₃₋₁₀ carbocycle substituted with 0-2 R^(3d) or a 5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-2R^(3d);

R^(3b) is, independently at each occurrence, H, C₁₋₆ alkyl substitutedwith 0-2 R^(3d), C₂₋₆ alkenyl substituted with 0-2 R^(3d), C₂₋₆ alkynylsubstituted with 0-2 R^(3d), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(3d);

R^(3c) is, independently at each occurrence, C₁₋₆ alkyl substituted with0-2 R^(3d), C₂₋₆ alkenyl substituted with 0-2 R^(3d), C₂₋₆ alkynylsubstituted with 0-2 R^(3d), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(3d);

R^(3d) is, independently at each occurrence, H, ═O, —(CH₂)_(r)OR^(a), F,Cl, Br, CN, NO₂, —(CH₂)_(r)NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷C(O)R^(b), —C(O)NR⁸R⁹, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂R^(c),—S(O)_(p)R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e),C₂₋₆ alkenyl substituted with 0-2 R^(e), C₂₋₆ alkynyl substituted with0-2 R^(e), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d);

R⁴ is, independently at each occurrence, H, ═O, F, Cl, Br, I, OCF₃, CF₃,OR^(a), SR^(a), CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸,—C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(4a), C₂₋₆alkenyl substituted with 0-2 R^(4a), C₂₋₆ alkynyl substituted with 0-2R^(4a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(4b), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(4b);

R^(4a) is, independently at each occurrence, H, F, ═O, C₁₋₆ alkyl,OR^(a), SR^(a), CF₃, CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)₂R^(c),—S(O)R^(c), or —S(O)₂R^(c);

R^(4b) is, independently at each occurrence, H, ═O, ═NR⁸, F, Cl, Br, I,OR^(a), SR^(a), CN, NO₂, CF₃, —SO₂R^(c), —NR⁷R⁸, —C(O)R^(a),—C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,C₁₋₄ haloalkyl, or C₁₋₄ haloalkoxy-;

alternately, R³ and R⁴ groups when located on adjacent atoms, can betaken together to form a C₃₋₁₀ carbocycle substituted with 0-2 R^(3d) ora 5- to 10-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(3d);

R⁵ is, independently at each occurrence, H, F, OCF₃, CF₃, OR^(a),SR^(a), CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸,—C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)₂R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(5a), C₂₋₆ alkenylsubstituted with 0-2 R^(5a), C₂₋₆ alkynyl substituted with 0-2 R^(5a),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(5b), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(5b);

R^(5a) is, independently at each occurrence, H, ═O, OR^(a), SR^(a), F,Cl, Br, I, CF₃, OCF₃, CN, NO₂, —NR⁷R⁸, —NR⁷R⁸, —C(O)NR⁷R⁸,—NR⁷C(O)R^(b), —S(O)₂NR⁸R⁹, —NR⁸S(O)₂R^(c), —S(O)R^(c), or —S(O)₂R^(c);

R^(5b) is, independently at each occurrence, H, ═O, ═NR⁸, F, Cl, Br, I,OR^(a), SR^(a), CN, NO₂, CF₃, —SO₂R^(c), —NR⁷R⁸, —C(O)R^(a),—C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)₂NR⁸R⁹, —S(O)₂R^(c), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄ haloalkoxy-;

R⁶ is, independently at each occurrence, H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,—CH₂OR^(a), —C(O)R^(c), —C(O)₂R^(c), —S(O)₂R^(c), or —(CH₂)_(r)-phenylsubstituted with 0-3 R^(d);

R⁷ is, independently at each occurrence, H, C₁₋₆ alkyl, —(CH₂)_(n)—C₃₋₁₀carbocycle, —(CH₂)_(n)-(5-10 membered heteroaryl), —C(O)R^(c), —CHO,—C(O)₂R^(c),

—S(O)₂R^(c), —CONR⁸R^(c), —OCONHR^(c), —C(O)O—(C₁₋₄ alkyl)OC(O)—(C₁₋₄alkyl), or —C(O)O—(C₁₋₄ alkyl)OC(O)—(C₆₋₁₀ aryl); wherein said alkyl,carbocycle, heteroaryl, and aryl are optionally substituted with 0-2R^(f);

R⁸ is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(r)-phenyl, or —(CH₂)_(n)-5-10 membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);wherein said alkyl, phenyl and heterocycle are optionally substitutedwith 0-2 R^(f);

alternatively, R⁷ and R⁸, when attached to the same nitrogen, combine toform a 5- to 10-membered heterocyclic ring comprising carbon atoms and0-2 additional heteroatoms selected from N, O, and S(O)_(p), whereinsaid heterocycle is substituted with 0-2 R^(d);

R^(8a) is, independently at each occurrence, H, OH, C₁₋₆ alkyl, C₁₋₄alkoxy, (C₆₋₁₀ aryl)-C₁₋₄ alkoxy, —(CH₂)_(n)-phenyl, —(CH₂)_(n)-(5-10membered heteroaryl), —C(O)R^(c), —C(O)₂R^(c), —C(O)O—(C₁₋₄alkyl)OC(O)—(C₁₋₄ alkyl), or —C(O)O—(C₁₋₄ alkyl)OC(O)—(C₆₋₁₀ aryl);wherein said phenyl, aryl, and heteroaryl is optionally substituted with0-2 R^(f);

R⁹ is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl; wherein said alkyl and phenyl are optionallysubstituted with 0-2 R^(f);

R^(9a) is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl;

alternatively, R⁸ and R⁹, when attached to the same nitrogen, combine toform a 5- to 10-membered heterocyclic ring comprising carbon atoms and0-2 additional heteroatoms selected from N, O, and S(O)_(p), whereinsaid heterocycle is substituted with 0-2 R^(d);

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-3 R^(10a), C₂₋₆ alkenyl substituted with 0-3 R^(10a), C₂₋₆ alkynylsubstituted with 0-3 R^(10a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(d);

R^(10a) is, independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a),SR^(a), F, CF₃, CN, NO₂, —C(O)OR^(a), —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸SO₂R^(c)—, —S(O)R^(c), or —S(O)₂R^(c);

R¹¹ is C₁₋₄ haloalkyl, —(CH₂)_(r)C(O)NR⁸R⁹, C₁₋₆ alkyl substituted with0-3 R^(11a), C₂₋₆ alkenyl substituted with 0-3 R^(11a), C₂₋₆ alkynylsubstituted with 0-3 R^(11a), —(CR¹⁴R¹⁵)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(11b), or —(CR¹⁴R¹⁵)_(r)-5- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p), wherein said heterocycle is substituted with 0-3R^(11b);

R^(11a) is, independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a),CF₃, SR^(a), F, CN, NO₂, NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —C(O)R^(a), —C(O)OR^(a),—S(O)_(p)R^(c) C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy-,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5-to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), and substituted with 0-3 R^(d);

R^(11b) is, independently at each occurrence, H, ═O, ═NR⁸, OR^(a), F,Cl, Br, CN, NO₂, CF₃, OCF₃, OCHF₂, —C(O)R^(a), —C(O)OR^(a), —SOR^(c),—SO₂R^(c), —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —NR⁸C(O)₂R^(c),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy-,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d);

alternately, when two R^(11b) groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-2R^(g);

R¹² is, independently at each occurrence, H, F, or C₁₋₄ alkyl;

R¹³ is, independently at each occurrence, H, C₁₋₆ alkyl,—(CH₂)_(n)-phenyl, —(CH₂)_(n)-(5-10 membered heteroaryl), —C(O)R^(c),—C(O)OR^(c), —CONR⁸R^(c), —OCONR⁸R^(c), —S(O)₂R^(c), —C(O)O—(C₁₋₄alkyl)-OC(O)—(C₁₋₄ alkyl), or —C(O)O—(C₁₋₄ alkyl)-OC(O)—(C₆₋₁₀ aryl);wherein the said alkyl, phenyl, heteroaryl, aryl are optionallysubstituted with 0-2 R^(f);

R¹⁴ and R¹⁵ are, independently at each occurrence, H, F, or C₁₋₄ alkyl;

-   -   alternately, R¹⁴ combines with R¹⁵ to form ═O;

R^(a) is, independently at each occurrence, H, CF₃, C₁₋₆ alkyl,—(CH₂)_(r)—C₃₋₇ cycloalkyl, —(CH₂)_(r)—C₆₋₁₀ aryl, or —(CH₂)_(r)-5- to10 membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p); wherein said cycloalkyl, aryl andheteroaryl groups are optionally substituted with 0-2 R^(f);

R^(b) is, independently at each occurrence, CF₃, OH, C₁₋₄ alkoxy, C₁₋₆alkyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d);

R^(c) is, independently at each occurrence, CF₃, C₁₋₆ alkyl substitutedwith 0-2 R^(f), C₃₋₆ cycloalkyl substituted with 0-2 R^(f), C₆₋₁₀ aryl,5- to 10-membered heteroaryl, (C₆₋₁₀ aryl)-C₁₋₄ alkyl, or (5- to10-membered heteroaryl)-C₁₋₄ alkyl, wherein said aryl and heteroarylgroups are optionally substituted with 0-3 R^(f);

R^(d) is, independently at each occurrence, H, ═O, ═NR⁸, OR^(a), F, Cl,Br, I, CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁸C(O)R^(a), —C(O)NR⁷R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl,—NR⁸SO₂CF₃, —NR⁸SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl,—S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e),C₂₋₆ alkenyl substituted with 0-2 R^(e), or C₂₋₆ alkynyl substitutedwith 0-2 R^(e);

R^(e) is, independently at each occurrence, ═O, OR^(a), F, Cl, Br, I,CN, NO₂, —NR⁸R⁹, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁸C(O)R^(a),—C(O)NR⁷R⁸, —SO₂NR⁸R⁹, NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl, —NR⁸SO₂CF₃,—NR⁸SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, or—(CF₂)_(r)CF₃;

R^(f) is, independently at each occurrence, H, ═O, —(CH₂)_(r)—OR^(g), F,Cl, Br, I, CN, NO₂, —NR^(9a)R^(9a), —C(O)R^(g), —C(O)OR^(g),—NR^(9a)C(O)R^(g), —C(O)NR^(9a)R^(9a), —SO₂NR^(9a)R^(9a),—NR^(9a)SO₂NR^(9a)R^(9a), —NR^(9a)SO₂—C₁₋₄ alkyl, —NR^(9a)SO₂CF₃,—NR^(9a)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl,—(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, or—(CH₂)_(n)-phenyl;

R^(g) is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl;

n, at each occurrence, is selected from 0, 1, 2, 3, and 4;

-   -   p, at each occurrence, is selected from 0, 1, and 2;    -   r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and

s, at each occurrence, is selected from 1, 2, 3, and 4;

-   -   provided that:

(a) when group

i. and when L is —NHC(O)—, R¹⁴ does not combine with R¹⁵ to form ═O;

ii. and when L is —C(O)NH— and A is phenyl, R¹ is not —NHC(O)H;

(b) when group

i. and when L is —NHC(O)— and R³ combines with R⁴ to form a phenyl ringfused with the thiazole, the phenyl ring is substituted with at leastone R^(3a);

ii. and when L is —C(O)NH— and A is phenyl, R¹ is not —NHC(O)H; and

(c) A is not a substituted or unsubstituted oxazolinone, thiophene,oxadiazole, or furan.

In a nineteenth aspect, the present invention includes compounds ofFormula (V), within the scope of the eighteenth aspect wherein:

A is C₃₋₈ cycloalkyl substituted with 0-1 R¹ and 0-3 R², C₄₋₈cycloalkenyl substituted with 0-1 R¹ and 0-3 R², phenyl substituted with0-1 R¹ and 0-3 R², naphthyl substituted with 0-1 R¹ and 0-3 R², or a 5-to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-1 R¹ and 0-3 R²; provided when A is a heterocyclecontaining one or more nitrogen atoms, A is not attached to L via any ofthe nitrogen atoms on the A ring;

Z is —C(R¹¹)(R¹²)—;

L is —C(O)NR¹⁰—, —NR¹⁰C(O)—, —CH₂C(O)NR¹⁰—, —CH₂NR¹⁰C(O)—,—C(O)NR¹⁰CH₂—, or —NR¹⁰C(O)CH₂—;

R³ is, independently at each occurrence, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)C(O)NR⁸(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)CO₂R^(3b),—(CH₂)_(r)—C₃₋₈ cycloalkyl substituted with 0-2 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-phenyl substituted with 0-3 R^(3c) and 0-1 R^(3d),—(CH₂)_(r)-naphthyl substituted with 0-3 R^(3c) and 0-1 R^(3d),—(CH₂)_(r)-indanyl substituted with 0-3 R^(3a) and 0-1 R^(3d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(3a) and 0-1 R^(3d);

R⁴ is H, F, Cl, Br, I, OCF₃, CF₃, OR^(a), SR^(a), CN, NO₂, —C(O)R^(a),—C(O)OR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with0-2 R^(4a), C₂₋₆ alkenyl substituted with 0-2 R^(4a), C₂₋₆ alkynylsubstituted with 0-2 R^(4a), phenyl substituted with 0-2 R^(4b), or a5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(4b);

R⁶ is, independently at each occurrence, H, C₁₋₆ alkyl, —CH₂OR^(a),—C(O)R^(c), —C(O)₂R^(c), or —(CH₂)_(r)-phenyl substituted with 0-3R^(d);

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-3 R^(10a), —(CH₂)_(r)-phenyl substituted with 0-3 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d); and

R¹¹ is C₁₋₄ haloalkyl, —(CH₂)_(r)C(O)NR⁸R⁹, C₁₋₆ alkyl substituted with0-3 R^(11a), C₂₋₆ alkenyl substituted with 0-3 R^(11a), C₂₋₆ alkynylsubstituted with 0-3 R^(11a), —(CH₂)—C₃₋₁₀ carbocycle substituted with0-3 R^(11b), or —(CH₂)_(r)-5-10 membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(11b).

In a twentieth aspect, the present invention includes compounds ofFormula (V), within the scope of the eighteenth aspect wherein:

A is C₅₋₆ cycloalkyl substituted with 0-1 R¹ and 0-2 R², C₅₋₆cycloalkenyl substituted with 0-1 R¹ and 0-2 R², phenyl substituted with0-1 R¹ and 0-3 R², naphthyl substituted with 0-1 R¹ and 0-3 R², or a 5-to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-1 R¹ and 0-3 R²; provided when A is a heterocyclecontaining one or more nitrogen atoms, A is not attached to L via any ofthe nitrogen atoms on the A ring;

R³ is, independently at each occurrence, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)C(O)NR⁸(CH₂)_(s)CO₂R^(3b), —(CH₂)_(r)CO₂R^(3b),—(CH₂)_(r)-phenyl substituted with 0-3 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-naphthyl substituted with 0-3 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-indanyl substituted with 0-3 R^(3a) and 0-1 R^(3d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(3a) and 0-1 R^(3d); and

R⁶ is, independently at each occurrence, H or C₁₋₆ alkyl.

In a twenty-first aspect, the present invention includes compounds ofFormula (V), within the scope of the eighteenth aspect wherein:

the group

is selected from:

In a twenty-second aspect, the present invention includes compounds ofFormula (V), within the scope of the eighteenth aspect wherein:

the group

is selected from:

In a twenty-third aspect, the present invention includes compounds ofFormula (V), within the scope of the eighteenth aspect wherein:

A is substituted with 0-1 R¹ and 0-2 R² and selected from: C₃₋₇cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, pyridyl,indazolyl, benzimidazolyl, benzisoxazolyl, isoquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,quinazolinyl, 1H-quinazolin-4-onyl, 2H-isoquinolin-1-onyl,3H-quinazolin-4-onyl, 3,4-dihydro-2H-isoquinolin-1-onyl,2,3-dihydroisoindolinonyl, and phthalazinyl;

the group

is selected from:

Z is —CH(R¹²)—;

L is —C(O)NR¹⁰—, —NR¹⁰C(O)—, —CH₂C(O)NR¹⁰—, —CH₂NR¹⁰C(O)—,—C(O)NR¹⁰CH₂—, or —NR¹⁰C(O)CH₂—;

R³ is, independently at each occurrence, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)C(O)NR⁸(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)CO₂R^(3b),—(CH₂)_(r)-phenyl substituted with 0-3 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-naphthyl substituted with 0-3 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-indanyl substituted with 0-3 R^(3a) and 0-1 R^(3d) or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), and substituted with 0-3R^(3a) and 0-1 R^(3d);

R⁴ is, independently at each occurrence, H, ═O, F, Cl, Br, I, OCF₃, CF₃,CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkylsubstituted with 0-2 R^(4a), C₂₋₆ alkenyl substituted with 0-2 R^(4a),C₂₋₆ alkynyl substituted with 0-2 R^(4a), phenyl substituted with 0-2R^(4b), or a 5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), and substituted with 0-3R^(4b);

R⁶ is H, C₁₋₆ alkyl, or —(CH₂)_(r)-phenyl substituted with 0-3 R^(d);

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-2 R^(10a), —(CH₂)_(r)-phenyl substituted with 0-2 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(d); and

R¹² is, independently at each occurrence, H, F, or Me.

In another aspect, the present invention includes compounds of Formula(V), within the scope of the twenty-second aspect wherein:

the group

In a twenty-fourth aspect, the present invention includes a compound ofFormula (VI):

or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the eighteenth aspectwherein:

R³ is —(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(s)C(O)NR⁸(CH₂)_(r)CO₂R^(3b),—(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)-phenyl substituted with 0-3 R^(3a) and0-1 R^(3d), —(CH₂)_(r)-naphthyl substituted with 0-2 R^(3a),—(CH₂)_(r)-indanyl substituted with 0-2 R^(3a), or —(CH₂)_(r)-5-10membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(3a) and 0-1 R^(3d);

R⁶ is, independently at each occurrence, H, C₁₋₆ alkyl, —CH₂OR^(a),—C(O)R^(c), —C(O)₂R^(c), or —(CH₂)_(r)-phenyl substituted with 0-3R^(d);

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-3 R^(10a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d); and

R¹¹ is C₁₋₄ haloalkyl, —(CH₂)_(r)C(O)NR⁸R⁹, C₁₋₆ alkyl substituted with0-3 R^(11a), C₂₋₆ alkenyl substituted with 0-3 R^(11a), C₂₋₆ alkynylsubstituted with 0-3 R^(11a), —(CH₂)—C₃₋₁₀ carbocycle substituted with0-3 R^(11b), or —(CH₂)_(r)-5-10 membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(11b).

In a twenty-fifth aspect, the present invention includes compounds ofFormula (VI), within the scope of the twenty-fourth aspect wherein:

R¹ is, independently at each occurrence, F, Cl, Me, Et, —NH₂,—C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂NHCO₂Bn, —CH₂NHCO₂(t-Bu),—CH(Me)NH₂, —CMe₂NH₂, —NHEt, —NHCO₂(t-Bu), —NHCO₂Bn, —SO₂NH₂, OR^(a), or—CH₂R^(1a);

R³ is —CO₂H, —CO₂Me, —C(O)NHCH₂CO₂H, —C(O)NHCH₂CO₂Et, —C(O)NH₂,—C(O)NHMe, —C(O)NHBn, —(CH₂)_(r)-phenyl substituted with 0-2 R^(3a) and0-1 R^(3d), naphthyl substituted with 0-2 R^(3a) and 0-1 R^(3d), indanylsubstituted with 0-2 R^(3a) and 0-1 R^(3d), or a —(CH₂)_(r)-5- to10-membered heterocycle comprising: carbon atoms and 1-2 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(3a) and 0-1 R^(3d);

R⁶ is H;

R¹⁰ is, independently at each occurrence, H, Me, benzyl, phenethyl,—CH₂CH₂CO₂H, —CH₂CH₂CO₂Me, —CH₂CH₂CO₂Et, —CH₂CH₂CONH₂, or—CH₂CH₂CONHCH₂CH₂Ph; and

R¹¹ is C₁₋₆ alkyl, —CH₂CONR⁸R⁹, —CH₂CH₂CONR⁸R⁹, —CH₂OBn, —CH₂SBn,—(CH₂)_(r)—C₃₋₇ cycloalkyl substituted with 0-2 R^(11b),—(CH₂)_(r)-phenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-naphthylsubstituted with 0-2 R^(11b), or —(CH₂)_(r)-5-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-2 R^(11b).

In a twenty-sixth aspect, the present invention includes a compound ofFormula (VII):

or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the eighteenth aspectwherein:

A is substituted with 0-2 R¹ and 0-1 R² and selected from: C₃₋₇cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, pyridyl,indazolyl, benzimidazolyl, benzisoxazolyl, isoquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,quinazolinyl, 1H-quinazolin-4-onyl, 2H-isoquinolin-1-onyl,3H-quinazolin-4-onyl, 3,4-dihydro-2H-isoquinolin-1-onyl,2,3-dihydroisoindolinonyl, and phthalazinyl;

L is —C(O)NH— or —NHC(O)—;

R¹ is, independently at each occurrence, F, Cl, Me, Et, —NH₂,—C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, —CH₂NHCO₂Bn, —CH₂NHCO₂(t-Bu), —CH(Me)NH₂,—CMe₂NH₂, —NHEt, —NHCO₂(t-Bu), —NHCO₂Bn, —SO₂NH₂, OR^(a), or —CH₂R^(1a);

R³ is —CO₂H, —CO₂Me, —C(O)NHCH₂CO₂H, —C(O)NHCH₂CO₂Et, —C(O)NH₂,—C(O)NHMe, —C(O)NHBn, phenyl substituted with 0-2 R^(3a), naphthylsubstituted with 0-2 R^(3a), indanyl substituted with 0-2 R^(3a), or a5- to 10-membered heterocycle comprising: carbon atoms and 1-2heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(3a);

R⁴ is H, F, Cl, Br, CF₃, CO₂H, CO₂Me, CO₂Et, C₁₋₆ alkyl substituted with0-2 R^(4a), phenyl substituted with 0-2 R^(4b), or 5-10 memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-2R^(4b);

R¹¹ is C₁₋₆ alkyl, —CH₂CONR⁸R⁹, —CH₂CH₂CONR⁸R⁹, —CH₂OBn, —CH₂SBn,—(CH₂)_(r)—C₃₋₇ cycloalkyl substituted with 0-2 R^(11b),—(CH₂)_(r)-phenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-naphthylsubstituted with 0-2 R^(11b), or —(CH₂)_(r)-5- to 10-membered heteroarylsubstituted with 0-2 R^(11b) and selected from thiazolyl, oxazolyl,triazolyl, tetrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, and tetrahydroisoquinolinyl; and

R^(11b) is, independently at each occurrence, H, F, Cl, Br, CF₃, OMe,OEt, O(i-Pr), OCF₃, OCHF₂, CN, OPh, OBn, NO₂, —NH₂, —C(O)R^(a),—C(O)OR^(a), —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —NR⁸C(O)₂R^(c), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —SO₂R^(c), C₁-C₄-alkyl, Ph, or Bn;

alternately, when two R^(11b) groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-2R^(g).

In a twenty-seventh aspect, the present invention includes compounds ofFormula (V), within the scope of the twenty-sixth aspect wherein:

A is 4-CH₂NH₂-cyclohexyl or 4-amidino-phenyl; and

R³ is phenyl, 3-CN-phenyl, 4-CN-phenyl, 3-Br-phenyl, 4-Br-phenyl,3-OMe-phenyl, 4-OMe-phenyl, 3-CF₃-phenyl, 4-CF₃-phenyl, 3-CO₂H-phenyl,4-CO₂H-phenyl, 4-CO₂Me-phenyl, 4-CH₂CO₂H-phenyl, 4-CH₂CO₂Me-phenyl,3-CONH₂-phenyl, 4-CONH₂-phenyl, 4-CONHMe-phenyl, 4-CON(Me)₂-phenyl,4-CH₂CONH₂-phenyl, 4-amidino-phenyl, or 2,4-diF-phenyl.

In a twenty-eighth aspect, the present invention includes, inter alia, amethod for treating a thromboembolic or an inflammatory disorder,comprising: administering to a patient in need thereof a therapeuticallyeffective amount of at least one compound of Formula (I):

or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

A is C₃₋₁₀ carbocycle substituted with 0-3 R¹ and 0-1 R², or a 5- to12-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R¹ and 0-1 R²;

L is —C(O)NR¹⁰—, —NR¹⁰C(O)—, —CH₂C(O)NR¹⁰—, —CH₂NR¹⁰C(O)—,—C(O)NR¹⁰CH₂—, —NR¹⁰C(O)CH₂—, —S(O)₂NR¹⁰—, —NR¹⁰S(O)₂—, —CH₂S(O)₂NR¹⁰—,—CH₂NR¹⁰S(O)₂—, —S(O)₂NR¹⁰CH₂—, —NR¹⁰S(O)₂CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂NR⁷—, —NR⁷CH₂—, —CH₂CH₂NR⁷—, —NR⁷CH₂CH₂, —CH₂NR⁷CH₂—, —CH₂O—,—OCH₂—, —CH₂S(O)_(p)—, —S(O)pCH₂—, —CH₂CH₂O—, —OCH₂CH₂—, —CH₂OCH₂—,—CH₂CH₂S(O)_(p)—, —S(O)_(p)CH₂CH₂—, —CH₂S(O)_(p)CH₂—, —CH₂C(O),—CH₂C(O)CH₂—, —CH₂CH₂C(O)—, —C(O)CH₂CH₂—, or —C(O)CH₂—;

R¹ is, independently at each occurrence, —NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —C(═NH)NH₂, —C(O)NR⁸R⁹, —S(O)_(p)NR⁸R⁹,—(CH₂)_(r)NR⁷R⁸, —(CH₂)_(r)NR⁷CO₂R^(a), —CH₂NH₂, —CH₂NH(C₁₋₃ alkyl),—CH₂N(C₁₋₃ alkyl)₂, —CH₂CH₂NH₂, —CH₂CH₂NH(C₁-C₃ alkyl), —CH₂CH₂N(C₁₋₃alkyl)₂, —CH(C₁₋₄ alkyl)NH₂, —C(C₁₋₄ alkyl)₂NH₂, —C(═NR^(8a))NR⁷R⁸,—NHC(═NR^(8a))NR⁷R⁸, ═NR⁸, —NR⁸CR⁸(═NR^(8a)), F, Cl, Br, I, OCF₃, CF₃,—(CH₂)_(r)OR^(a), —(CH₂)_(r)SR^(a), CN, 1-NH₂-1-cyclopropyl, or C₁₋₆alkyl substituted with 0-1 R^(1a);

R^(1a) is H, —C(═NR^(8a))NR⁷R⁸, —NHC(═NR^(8a))NR⁷R⁸, —NR⁸CH(═NR^(8a)),—NR⁷R⁸, —C(O)NR⁸R⁹, F, OCF₃, CF₃, OR^(a), SR^(a), CN, —NR⁹SO₂NR⁸R⁹,—NR⁸SO₂R^(c), —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, or —(CF₂)_(r)CF₃;

R² is, independently at each occurrence, H, ═O, F, Cl, Br, I, OCF₃, CF₃,CHF₂, CN, NO₂, OR^(a), SR^(a), —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —S(O)₂NR⁸R⁹, —NR⁸S(O)₂R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(2a), C₂₋₆alkenyl substituted with 0-2 R^(2a), C₂₋₆ alkynyl substituted with 0-2R^(2a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(2b), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(2b);

R^(2a) is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸,CN, OCF₃, CF₃, OR^(a), SR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸SO₂R^(c), —S(O)R^(c), or —S(O)₂R^(c);

R^(2b) is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸,CN, NO₂, CF₃, OR^(a), SR^(a), —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —S(O)₂NR⁸R⁹, —S(O)₂R^(c),—NR⁸SO₂NR⁸R⁹, —NR⁸SO₂R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄ haloalkoxy-;

alternately, when R¹ and R² groups are substituted on adjacent ringatoms, they can be taken together with the ring atoms to which they areattached to form a 5- to 7-membered carbocycle or heterocyclecomprising: carbon atoms and 0-4 heteroatoms selected from N, O, andS(O)_(p), wherein said carbocycle or heterocycle is substituted with 0-2R^(2b);

R³ is F, Cl, Br, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)C(O)NR⁸(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)CO₂R^(3b), —(CH₂)—C₃₋₁₀carbocycle substituted with 0-3 R^(3a) and 0-1 R^(3d), or —(CH₂)_(r)-5-to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(3a) and 0-1 R^(3d);

R^(3a) is, independently at each occurrence, ═O, F, Cl, Br, I, OCF₃,CF₃, NO₂, CN, —(CH₂)_(r)OR^(3b), SR^(3b), —(CH₂)_(r)NR⁷R⁸,C(═NR^(8a))NR⁸R⁹, —NHC(═NR^(8a))NR⁷R⁸, —NR⁸CR⁸(═NR^(8a)),—(CH₂)_(r)NR⁸C(O)R^(3b), ═NR⁸, —(CH₂)_(r)NR⁸C(O)R^(3b),—(CH₂)_(r)NR⁸C(O)₂R^(3b), —(CH₂)_(r)S(O)_(p)NR⁸R⁹,—(CH₂)_(r)NR⁸S(O)_(p)R^(3c), —S(O)_(p)R^(3c), —S(O)_(p)R^(3c), C₁₋₄alkyl-C(O)—, —(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)OC(O)NR⁸R⁹, —NHCOCF₃, —NHSO₂CF₃, —SO₂NHR^(3b), —SO₂NHCOR^(3c),—SO₂NHCO₂R^(3c), —CONHSO₂R^(3c), —NHSO₂R^(3c), —CONHOR^(3b), C₁₋₄haloalkyl, C₁₋₄ haloalkoxy-, C₁₋₆ alkyl substituted by R^(3d), C₂₋₆alkenyl substituted by R^(3d), C₂₋₆ alkynyl substituted by R^(3d), C₃₋₆cycloalkyl substituted by 0-1 R^(3d), —(CH₂)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(3d);

alternately, when two R^(3c) groups are located on adjacent atoms, theycan be taken together with the atoms to which they are attached to forma C₃₋₁₀ carbocycle substituted with 0-2 R^(3d) or a 5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-2R^(3d);

R^(3b) is, independently at each occurrence, H, C₁₋₆ alkyl substitutedwith 0-2 R^(3d), C₂₋₆ alkenyl substituted with 0-2 R^(3d), C₂₋₆ alkynylsubstituted with 0-2 R^(3d), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(3d);

R^(3c) is, independently at each occurrence, C₁₋₆ alkyl substituted with0-2 R^(3d), C₂₋₆ alkenyl substituted with 0-2 R^(3d), C₂₋₆ alkynylsubstituted with 0-2 R^(3d), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(3d);

R^(3d) is, independently at each occurrence, H, ═O, —(CH₂)_(r)OR^(a), F,Cl, Br, CN, NO₂, —(CH₂)_(r)NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷C(O)R^(b), —C(O)NR⁸R⁹, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂R^(c),—S(O)_(p)R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e),C₂₋₆ alkenyl substituted with 0-2 R^(e), C₂₋₆ alkynyl substituted with0-2 R^(e), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d);

R⁴ is H, ═O, F, Cl, Br, I, OCF₃, CF₃, OR^(a), SR^(a), CN, NO₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkylsubstituted with 0-2 R^(4a), C₂₋₆ alkenyl substituted with 0-2 R^(4a),C₂₋₆ alkynyl substituted with 0-2 R^(4a), —(CH₂)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(4b), or —(CH₂)_(r)-5- to 10-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(4b);

R^(4a) is, independently at each occurrence, H, F, ═O, C₁₋₆ alkyl,OR^(a), SR^(a), CF₃, CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)₂R^(c),—S(O)R^(c), or —S(O)₂R^(c);

R^(4b) is, independently at each occurrence, H, ═O, ═NR⁸, F, Cl, Br, I,OR^(a), SR^(a), CN, NO₂, CF₃, —SO₂R^(c), —NR⁷R⁸, —C(O)R^(a),—C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,C₁₋₄ haloalkyl, or C₁₋₄ haloalkoxy-;

alternately, R³ and R⁴ groups when located on adjacent atoms, can betaken together to form a C₃₋₁₀ carbocycle substituted with 0-2 R^(3d) ora 5- to 10-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(3d);

R⁶ is, independently at each occurrence, H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,—CH₂OR^(a), —C(O)R^(c), —C(O)₂R^(c), —S(O)₂R^(c), or —(CH₂)_(r)-phenylsubstituted with 0-3 R^(d);

R⁷ is, independently at each occurrence, H, C₁₋₆ alkyl, —(CH₂)_(n)—C₃₋₁₀carbocycle, —(CH₂)_(n)-(5-10 membered heteroaryl), —C(O)R^(c), —CHO,—C(O)₂R^(c), —S(O)₂R^(c), —CONR⁸R^(c), —OCONHR^(c), —C(O)O—(C₁₋₄alkyl)OC(O)—(C₁₋₄ alkyl), or —C(O)O—(C₁₋₄ alkyl)OC(O)—(C₆₋₁₀ aryl);wherein said alkyl, carbocycle, heteroaryl, and aryl are optionallysubstituted with 0-2 R^(f);

R⁸ is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl, or —(CH₂)_(n)-5-10 membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);wherein said alkyl, phenyl and heterocycle are optionally substitutedwith 0-2 R^(f);

alternatively, R⁷ and R⁸, when attached to the same nitrogen, combine toform a 5- to 10-membered heterocyclic ring comprising carbon atoms and0-2 additional heteroatoms selected from N, O, and S(O)_(p), whereinsaid heterocycle is substituted with 0-2 R^(d);

R^(8a) is, independently at each occurrence, H, OH, C₁₋₆ alkyl, C₁₋₄alkoxy, (C₆₋₁₀ aryl)-C₁₋₄ alkoxy, —(CH₂)_(n)-phenyl, —(CH₂)_(n)-(5-10membered heteroaryl), —C(O)R^(c), —C(O)₂R^(c), —C(O)O—(C₁₋₄alkyl)OC(O)—(C₁₋₄ alkyl), or —C(O)O—(C₁₋₄ alkyl)OC(O)—(C₆₋₁₀ aryl);wherein said phenyl, aryl, and heteroaryl is optionally substituted with0-2 R^(f);

R⁹ is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(r)-phenyl; wherein said alkyl and phenyl are optionallysubstituted with 0-2 R^(f);

R^(9a) is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(r)-phenyl;

alternatively, R⁸ and R⁹, when attached to the same nitrogen, combine toform a 5- to 10-membered heterocyclic ring comprising carbon atoms and0-2 additional heteroatoms selected from N, O, and S(O)_(p), whereinsaid heterocycle is substituted with 0-2 R^(d);

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-3 R^(10a), C₂₋₆ alkenyl substituted with 0-3 R^(10a), C₂₋₆ alkynylsubstituted with 0-3 R^(10a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(d);

R^(10a) is, independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a),SR^(a), F, CF₃, CN, NO₂, —C(O)OR^(a), —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸SO₂R^(c)—, —S(O)R^(c) or —S(O)₂R^(c);

R¹¹ is C₁₋₄ haloalkyl, —(CH₂)_(r)C(O)NR⁸R⁹, C₁₋₆ alkyl substituted with0-3 R^(11a), C₂₋₆ alkenyl substituted with 0-3 R^(11a), C₂₋₆ alkynylsubstituted with 0-3 R^(11a), —(CR¹⁴R¹⁵)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(11b), or —(CR¹⁴R¹⁵)_(r)-5- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p), wherein said heterocycle is substituted with 0-3R^(11b);

R^(11a) is, independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a),CF₃, SR^(a), F, CN, NO₂, —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —C(O)R^(a), —C(O)OR^(a),—S(O)_(p)R^(c), C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy-,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5-to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), and substituted with 0-3 R^(d);

R^(11b) is, independently at each occurrence, H, ═O, ═NR⁸, OR^(a), F,Cl, Br, CN, NO₂, CF₃, OCF₃, OCHF₂, —C(O)R^(a), —C(O)OR^(a), —SOR^(c),—SO₂R^(c), —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —NR⁸C(O)₂R^(c),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy-,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d);

alternately, when two R^(11b) groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-2R^(g);

R¹⁴ and R¹⁵ are, independently at each occurrence, H, F, or C₁₋₄ alkyl;

-   -   alternately, R¹⁴ combines with R¹⁵ to form ═O;

R^(a) is, independently at each occurrence, H, CF₃, C₁₋₆ alkyl,—(CH₂)_(r)C₃₋₇ cycloalkyl, —(CH₂)_(r)—C₆₋₁₀ aryl, or —(CH₂)_(r)-5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p); wherein said cycloalkyl, aryl andheterocycle groups are optionally substituted with 0-2 R^(f);

R^(b) is, independently at each occurrence, CF₃, OH, C₁₋₄ alkoxy, C₁₋₆alkyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d);

R^(c) is, independently at each occurrence, CF₃, C₁₋₆ alkyl substitutedwith 0-2 R^(f), C₃₋₆ cycloalkyl substituted with 0-2 R^(f), C₆₋₁₀ aryl,5- to 10-membered heteroaryl, (C₆₋₁₀ aryl)-C₁₋₄ alkyl, or (5- to10-membered heteroaryl)-C₁₋₄ alkyl, wherein said aryl and heteroarylgroups are optionally substituted with 0-3 R^(f);

R^(d) is, independently at each occurrence, H, ═O, ═NR⁸, OR^(a), F, Cl,Br, I, CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁸C(O)R^(a), —C(O)NR⁷R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl,—NR⁸SO₂CF₃, —NR⁸SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl,—S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e),C₂₋₆ alkenyl substituted with 0-2 R^(e), or C₂₋₆ alkynyl substitutedwith 0-2 R^(e);

R^(e) is, independently at each occurrence, ═O, OR^(a), F, Cl, Br, I,CN, NO₂, —NR⁸R⁹, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁸C(O)R^(a),—C(O)NR⁷R⁸, —SO₂NR⁸R⁹, NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl, —NR⁸SO₂CF₃,—NR⁸SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, or—(CF₂)_(r)CF₃;

R^(f) is, independently at each occurrence, H, ═O, —(CH₂)_(r)—OR^(g), F,Cl, Br, I, CN, NO₂, —NR^(9a)R^(9a), —C(O)R^(g), —C(O)OR^(g),—NR^(9a)C(O)R^(g), —C(O)NR^(9a)R^(9a), —SO₂NR^(9a)R^(9a),—NR^(9a)SO₂NR^(9a)R^(9a), —NR^(9a)SO₂—C₁₋₄ alkyl, —NR^(9a)SO₂CF₃,—NR^(9a)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl,—(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, or—(CH₂)_(n)-phenyl;

R^(g) is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl;

n, at each occurrence, is selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is selected from 0, 1, and 2;

r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and

s, at each occurrence, is selected from 1, 2, 3, and 4.

In a twenty-ninth aspect, the present invention provides a method fortreating a thromboembolic or an inflammatory disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of at least one compound of Formula (I), within the scope of thetwenty-eighth aspect wherein:

L is —C(O)NR¹⁰—, —NR¹⁰C(O)—, —CH₂CONR¹⁰—, or —NR¹⁰COCH₂—;

R³ is —(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(r)C(O)NR⁸(CH₂)_(s)CO₂R^(3b),—(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)-phenyl substituted with 0-3 R^(3a) and0-1 R^(3d), —(CH₂)_(r)-naphthyl substituted with 0-3 R^(3a) and 0-1R^(3d), —(CH₂)_(r)-indanyl substituted with 0-3 R^(3a) and 0-1 R^(3d),or —(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(3a) and 0-1 R^(3d);

R⁴ is H, F, Cl, Br, I, OCF₃, CF₃, OR^(a), SR^(a), CN, NO₂, —C(O)R^(a),—C(O)OR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with0-2 R^(4a), C₂₋₆ alkenyl substituted with 0-2 R^(4a), C₂₋₆ alkynylsubstituted with 0-2 R^(4a), phenyl substituted with 0-2 R^(4b), or a5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(4b);

R⁶ is H, C₁₋₆ alkyl, —CH₂OR^(a), or —(CH₂)_(r)-phenyl substituted with0-3 R^(d);

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-2 R^(10a), —(CH₂)_(r)-phenyl substituted with 0-2 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(d); and

R¹¹ is C₁₋₄ haloalkyl, —(CH₂)_(r)—CONR⁸R⁹, C₁₋₆ alkyl substituted with0-2 R^(11a), C₂₋₆ alkenyl substituted with 0-2 R^(11a), C₂₋₆ alkynylsubstituted with 0-2 R^(11a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(11b), or —(CH₂)_(r)-5-10 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(11b).

In a thirtieth aspect, the present invention provides a method fortreating a thromboembolic or an inflammatory disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of at least one compound of Formula (I), within the scope of thetwenty-eighth aspect wherein:

R¹ is, independently at each occurrence, F, Cl, Me, Et, —NH₂,—C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂NHCO₂Bn, —CH₂NHCO₂(t-Bu),—CH(Me)NH₂, —C(Me)₂NH₂, —NHEt, —NHCO₂(t-Bu), —NHCO₂Bn, —SO₂NH₂, OR^(a),or —CH₂OR^(1a);

R³ is —CO₂H, —CO₂Me, —C(O)NHCH₂CO₂H, —C(O)NHCH₂CO₂Et, —C(O)NH₂,—C(O)NHMe, —C(O)NHBn, —(CH₂)_(r)-phenyl substituted with 0-2 R^(3a) and0-1 R^(3d), naphthyl substituted with 0-2 R^(3a) and 0-1 R^(3d), indanylsubstituted with 0-2 R^(3a) and 0-1 R^(3d), or —(CH₂)_(r)-5-10 memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-2R^(3a) and 0-1 R^(3d);

R⁴ is H, F, Cl, Br, OMe, NH₂, CF₃, CO₂H, CO₂Me, CO₂Et, —CONR⁸R⁹, C₁₋₆alkyl substituted with 0-2 R^(4a), phenyl substituted with 0-2 R^(4b),or a 5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(4b);

R⁶ is H, Me, benzyl, or phenethyl;

R¹⁰ is, independently at each occurrence, H, Me, benzyl, phenethyl,—CH₂CH₂CO₂H, —CH₂CH₂CO₂Me, —CH₂CH₂CO₂Et, —CH₂CH₂CONH₂, or—CH₂CH₂CONHCH₂CH₂Ph; and

R¹¹ is C₁₋₆ alkyl, —CH₂CONR⁸R⁹, —CH₂CH₂CONR⁸R⁹, —CH₂OBn, —CH₂SBn,—(CH₂)_(r)—C₃₋₇ cycloalkyl substituted with 0-2 R^(11b),—(CH₂)_(r)-phenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-naphthylsubstituted with 0-2 R^(11b), or —(CH₂)_(r)-5-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-2 R^(11b).

In a thirty-first aspect, the present invention provides a method fortreating a thromboembolic or an inflammatory disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of at least one compound of Formula (II):

or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the twenty-eighthaspect wherein:

A is substituted with 0-1 R¹ and 0-2 R² and selected from: C₃₋₇cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, pyridyl,indazolyl, benzimidazolyl, benzisoxazolyl, isoquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,quinazolinyl, 1H-quinazolin-4-onyl, 2H-isoquinolin-1-onyl,3H-quinazolin-4-onyl, 3,4-dihydro-2H-isoquinolin-1-onyl,2,3-dihydroisoindolinonyl, and phthalazinyl;

L is —C(O)NH—, —C(O)NMe-, —C(O)N(benzyl)-, —C(O)N(phenethyl)-, —NHC(O)—,—S(O)₂NH—, —CH₂C(O)NH—, —C(O)NHCH₂—, —CH₂NHC(O)— or —NHC(O)CH₂—;

R¹ is, independently at each occurrence, F, Cl, Me, Et, —NH₂,—C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, —CH₂NHCO₂Bn, —CH₂NHCO₂(t-Bu), —CH(Me)NH₂,—CMe₂NH₂, —NHEt, —NHCO₂(t-Bu), —NHCO₂Bn, —SO₂NH₂, OR^(a), or —CH₂R^(1a);

R³ is —CO₂H, —CO₂Me, —C(O)NHCH₂CO₂H, —C(O)NHCH₂CO₂Et, —C(O)NH₂,—C(O)NHMe, —C(O)NHBn, phenyl substituted with 0-2 R^(3a), naphthylsubstituted with 0-2 R^(3a), indanyl substituted with 0-2 R^(3a), or a5- to 10-membered heterocycle comprising: carbon atoms and 1-2heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(3a);

R⁴ is H, F, Cl, Br, OMe, NH₂, CF₃, CO₂H, CO₂Me, CO₂Et, C₁₋₆ alkylsubstituted with 0-2 R^(4a), phenyl substituted with 0-2 R^(4b), or 5-10membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(4b);

R¹¹ is C₁₋₆ alkyl, —CH₂CONR⁸R⁹, —CH₂CH₂CONR⁸R⁹, —CH₂OBn, —CH₂SBn,—(CH₂)_(r)—C₃₋₇ cycloalkyl substituted with 0-2 R^(11b),—(CH₂)_(r)-phenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-naphthylsubstituted with 0-2 R^(11b), or —(CH₂)_(r)-5- to 10-membered heteroarylsubstituted with 0-2 R^(11b) and selected from thiazolyl, oxazolyl,triazolyl, tetrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, and tetrahydroisoquinolinyl; and

R^(11b) is, independently at each occurrence, H, F, Cl, Br, CF₃, OMe,OEt, O(i-Pr), OCF₃, OCHF₂, CN, OPh, OBn, NO₂, —NH₂, —C(O)R^(a),—C(O)OR^(a), —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —NR⁸C(O)₂R^(c), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —SO₂R^(c), C₁-C₄-alkyl, Ph, or Bn;

alternately, when two R^(11b) groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-2R^(g).

In a thirty-second aspect, the present invention provides, inter alia, amethod for treating a thromboembolic or an inflammatory disorder,comprising: administering to a patient in need thereof a therapeuticallyeffective amount of at least one compound of Formula (V):

or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

A is C₃₋₁₀ carbocycle substituted with 0-3 R¹ and 0-1 R², or a 5- to12-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R¹ and 0-1 R²;

X¹, X², and X³ are independently CR³, CR⁴, CR⁴R⁵, O, S(O)_(p), N, NR³,NR⁶, or C(O); provided that no S—S, S—O, or O—O bond is present in thering;

provided that

is other than

Z is —C(R¹¹)(R¹²)—, —C(R¹¹)(R¹²)—(CH₂)—, —NR¹³—, or —NR¹³CH₂—;

L is —C(O)NR¹⁰—, —NR¹⁰C(O)—, —CH₂C(O)NR¹⁰—, —CH₂NR¹⁰C(O)—,—C(O)NR¹⁰CH₂—, —NR¹⁰C(O)CH₂—, —S(O)₂NR¹⁰—, —NR¹⁰S(O)₂—, —CH₂S(O)₂NR¹⁰—,—CH₂NR¹⁰S(O)₂—, —S(O)₂NR¹⁰CH₂—, —NR¹⁰S(O)₂CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂NR⁷—, —NR⁷CH₂—, —CH₂CH₂NR⁷—, —NR⁷CH₂CH₂, —CH₂NR⁷CH₂—, —CH₂O—,—OCH₂—, —CH₂S(O)_(p)—, —S(O)pCH₂—, —CH₂CH₂O—, —OCH₂CH₂—, —CH₂OCH₂—,—CH₂CH₂S(O)_(p)—, —S(O)_(p)CH₂CH₂—, —CH₂S(O)_(p)CH₂—, —CH₂C(O),—CH₂C(O)CH₂—, —CH₂CH₂C(O)—, —C(O)CH₂CH₂—, or —C(O)CH₂—;

R¹ is, independently at each occurrence, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃alkyl)₂, —C(═NH)NH₂, —C(O)NR⁸R⁹, —S(O)_(p)NR⁸R⁹, —(CH₂)_(r)NR⁷R⁸,—(CH₂)_(r)NR⁷C(O)OR^(a), —CH₂NH₂, —CH₂NH(C₁₋₃ alkyl), —CH₂N(C₁₋₃alkyl)₂, —CH₂CH₂NH₂, —CH₂CH₂NH(C₁₋₃ alkyl), —CH₂CH₂N(C₁₋₃ alkyl)₂,—CH(C₁₋₄ alkyl)NH₂, —C(C₁₋₄ alkyl)₂NH₂, —C(═NR^(8a))NR⁷R⁸,—NHC(═NR^(8a))NR⁷R⁸, ═NR⁸, —NR⁸CR⁸(═NR^(8a)), F, Cl, Br, I, OCF₃, CF₃,—(CH₂)_(r)OR^(a), —(CH₂)_(r)SR^(a), CN, 1-NH₂-1-cyclopropyl, or C₁₋₆alkyl substituted with 0-1 R^(1a);

R^(1a) is H, —C(═NR^(8a))NR⁷R⁸, —NHC(═NR^(8a))NR⁷R⁸, —NR⁸CH(═NR^(8a)),—NR⁷R⁸, —C(O)NR⁸R⁹, F, OCF₃, CF₃, OR^(a), SR^(a), CN, —NR⁹SO₂NR⁸R⁹,—NR⁸SO₂R^(c), —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, or —(CF₂)_(r)CF₃;

R² is, independently at each occurrence, H, ═O, F, Cl, Br, I, OCF₃, CF₃,CHF₂, CN, NO₂, OR^(a), SR^(a), —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —S(O)₂NR⁸R⁹, —NR⁸S(O)₂R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(2a), C₂₋₆alkenyl substituted with 0-2 R^(2a), C₂₋₆ alkynyl substituted with 0-2R^(2a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(2b), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(2b);

R^(2a) is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸,CN, OCF₃, CF₃, OR^(a), SR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸SO₂R^(c), —S(O)R^(c), or —S(O)₂R^(c);

R^(2b) is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸,CN, NO₂, CF₃, OR^(a), SR^(a), —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —S(O)₂NR⁸R⁹, —S(O)₂R^(c),—NR⁸SO₂NR⁸R⁹, —NR⁸SO₂R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄ haloalkoxy;

alternately, when R¹ and R² groups are substituted on adjacent ringatoms, they can be taken together with the ring atoms to which they areattached to form a 5- to 7-membered carbocycle or heterocyclecomprising: carbon atoms and 0-4 heteroatoms selected from N, O, andS(O)_(p), wherein said carbocycle or heterocycle is substituted with 0-2R²¹);

R³ is, independently at each occurrence, F, Cl, Br, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)C(O)NR⁸(CH₂)_(s)CO₂R^(3b), —(CH₂)_(r)CO₂R^(3b),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(3a) and 0-1 R^(3d),or —(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(3a) and 0-1 R^(3d);

R^(3a) is, independently at each occurrence, ═O, F, Cl, Br, I, OCF₃,CF₃, NO₂, CN, —(CH₂)_(r)OR^(3b), SR^(3b), —(CH₂)_(r)NR⁷R⁸,C(═NR^(8a))NR⁸R⁹, —NHC(═NR^(8a))NR⁷R⁸, —NR⁸CR⁸(═NR^(8a)),—(CH₂)_(r)NR⁸C(O)R^(3b), ═NR⁸, —(CH₂)_(r)NR⁸C(O)R^(3b),—(CH₂)_(r)NR⁸C(O)₂R^(3b), —(CH₂)_(r)S(O)_(p)NR⁸R⁹,—(CH₂)_(r)NR⁸S(O)_(p)R^(3c), —S(O)_(p)R^(3c), —S(O)_(p)R^(3c), C₁₋₄alkyl-C(O)—, —(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)OC(O)NR⁸R⁹, —NHCOCF₃, —NHSO₂CF₃, —SO₂NHR^(3b), —SO₂NHCOR^(3c),—SO₂NHCO₂R^(3c), —CONHSO₂R^(3c), —NHSO₂R^(3c), —CONHOR^(3b), C₁₋₄haloalkyl, C₁₋₄ haloalkoxy-, C₁₋₆ alkyl substituted by R^(3d), C₂₋₆alkenyl substituted by R^(3d), C₂₋₆ alkynyl substituted by R^(3d), C₃₋₆cycloalkyl substituted by 0-1 R^(3d), —(CH₂)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(3d);

alternately, when two R^(3a) groups are located on adjacent atoms, theycan be taken together with the atoms to which they are attached to forma C₃₋₁₀ carbocycle substituted with 0-2 R^(3d) or a 5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-2R^(3d);

R^(b) is, independently at each occurrence, H, C₁₋₆ alkyl substitutedwith 0-2 R^(3d), C₂₋₆ alkenyl substituted with 0-2 R^(3d), C₂₋₆ alkynylsubstituted with 0-2 R^(3d), —(CH₂)—C₃₋₁₀ carbocycle substituted with0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(3d);

R^(3c) is, independently at each occurrence, C₁₋₆ alkyl substituted with0-2 R^(3d), C₂₋₆ alkenyl substituted with 0-2 R^(3d), C₂₋₆ alkynylsubstituted with 0-2 R^(3d), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(3d);

R^(3d) is, independently at each occurrence, H, ═O, —(CH₂)_(r)OR^(a), F,Cl, Br, CN, NO₂, —(CH₂)_(r)NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷C(O)R^(b), —C(O)NR⁸R⁹, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂R^(e),—S(O)_(p)R^(e), —(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e),C₂₋₆ alkenyl substituted with 0-2 R^(e), C₂₋₆ alkynyl substituted with0-2 R^(e), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d);

R⁴ is, independently at each occurrence, H, ═O, F, Cl, Br, I, OCF₃, CF₃,OR^(a), SR^(a), CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸,—C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(4a), C₂₋₆alkenyl substituted with 0-2 R^(4a), C₂₋₆ alkynyl substituted with 0-2R^(4a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(4b), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(4b);

R^(4a) is, independently at each occurrence, H, F, ═O, C₁₋₆ alkyl,OR^(a), SR^(a), CF₃, CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)₂R^(c),—S(O)R^(c), or —S(O)₂R^(c);

R^(4b) is, independently at each occurrence, H, ═O, ═NR⁸, F, Cl, Br, I,OR^(a), SR^(a), CN, NO₂, CF₃, —SO₂R^(c), —NR⁷R⁸, —C(O)R^(a),—C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,C₁₋₄ haloalkyl, or C₁₋₄ haloalkoxy-;

alternately, R³ and R⁴ groups when located on adjacent atoms, can betaken together to form a C₃₋₁₀ carbocycle substituted with 0-2 R^(3d) ora 5- to 10-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(3d);

R⁵ is, independently at each occurrence, H, F, OCF₃, CF₃, OR^(a),SR^(a), CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸,—C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)₂R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(5a), C₂₋₆ alkenylsubstituted with 0-2 R^(5a), C₂₋₆ alkynyl substituted with 0-2 R^(5a),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(5b), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(5b);

R^(5a) is, independently at each occurrence, H, ═O, OR^(a), SR^(a), F,Cl, Br, I, CF₃, OCF₃, CN, NO₂, —NR⁷R⁸, —NR⁷R⁸, —C(O)NR⁷R⁸,—NR⁷C(O)R^(b), —S(O)₂NR⁸R⁹, —NR⁸S(O)₂R^(c), —S(O)R^(c), or —S(O)₂R^(c);

R^(5b) is, independently at each occurrence, H, ═O, ═NR⁸, F, Cl, Br, I,OR^(a), SR^(a), CN, NO₂, CF₃, —SO₂R^(c), —NR⁷R⁸, —C(O)R^(a),—C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)₂NR⁸R⁹, —S(O)₂R^(c), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₁-4 haloalkyl, or C₁₋₄ haloalkoxy-;

R⁶ is, independently at each occurrence, H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,—CH₂OR^(a), —C(O)R^(c), —C(O)₂R^(c), —S(O)₂R^(c), or —(CH₂)_(r)-phenylsubstituted with 0-3 R^(3d);

R⁷ is, independently at each occurrence, H, C₁₋₆ alkyl, —(CH₂)_(n)—C₃₋₁₀carbocycle, —(CH₂)_(n)-(5-10 membered heteroaryl), —C(O)R^(c), —CHO,—C(O)₂R^(c), —S(O)₂R^(c), —CONR⁸R^(c), —OCONHR^(c), —C(O)O—(C₁₋₄alkyl)OC(O)—(C₁₋₄ alkyl), or —C(O)O—(C₁₋₄ alkyl)OC(O)—(C₆₋₁₀ aryl);wherein said alkyl, carbocycle, heteroaryl, and aryl are optionallysubstituted with 0-2 R^(f);

R⁸ is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(r)-phenyl, or —(CH₂)_(n)-5-10 membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);wherein said alkyl, phenyl and heterocycle are optionally substitutedwith 0-2 R^(f);

alternatively, R⁷ and R⁸, when attached to the same nitrogen, combine toform a 5- to 10-membered heterocyclic ring comprising carbon atoms and0-2 additional heteroatoms selected from N, O, and S(O)_(p), whereinsaid heterocycle is substituted with 0-2 R^(d);

R^(8a) is, independently at each occurrence, H, OH, C₁₋₆ alkyl, C₁₋₄alkoxy, (C₆₋₁₀ aryl)-C₁₋₄ alkoxy, —(CH₂)_(n)-phenyl, —(CH₂)_(n)-(5-10membered heteroaryl), —C(O)R^(c), —C(O)₂R^(c), —C(O)O—(C₁₋₄alkyl)OC(O)—(C₁₋₄ alkyl), or —C(O)O—(C₁₋₄ alkyl)OC(O)—(C₆₋₁₀ aryl);wherein said phenyl, aryl, and heteroaryl is optionally substituted with0-2 R^(f);

R⁹ is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl; wherein said alkyl and phenyl are optionallysubstituted with 0-2 R^(f);

R^(9a) is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl;

alternatively, R⁸ and R⁹, when attached to the same nitrogen, combine toform a 5- to 10-membered heterocyclic ring comprising carbon atoms and0-2 additional heteroatoms selected from N, O, and S(O)_(p), whereinsaid heterocycle is substituted with 0-2 R^(d);

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-3 R^(10a), C₂₋₆ alkenyl substituted with 0-3 R^(10a), C₂₋₆ alkynylsubstituted with 0-3 R^(10a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(d);

R^(10a) is, independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a),SR^(a), F, CF₃, CN, NO₂, —C(O)OR^(a), —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸SO₂R^(c)—, —S(O)R^(c), or —S(O)₂R^(c);

R¹¹ is C₁₋₄ haloalkyl, —(CH₂)_(r)C(O)NR⁸R⁹, C₁₋₆ alkyl substituted with0-3 R^(11a), C₂₋₆ alkenyl substituted with 0-3 R^(11a), C₂₋₆ alkynylsubstituted with 0-3 R^(11a), —(CR¹⁴R¹⁵)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(11b), or —(CR¹⁴R¹⁵)_(r)-5- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p), wherein said heterocycle is substituted with 0-3R^(11b);

R^(11a) is, independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a),CF₃, SR^(a), F, CN, NO₂, —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —C(O)R^(a), —C(O)OR^(a),—S(O)_(p)R^(c), C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy-,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5-to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), and substituted with 0-3 R^(d);

R^(11b) is, independently at each occurrence, H, ═O, ═NR⁸, OR^(a), F,Cl, Br, CN, NO₂, CF₃, OCF₃, OCHF₂, —C(O)R^(a), —C(O)OR^(a), —SOR^(c),—SO₂R^(c), —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —NR⁸C(O)₂R^(c),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy-,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d);

alternately, when two R^(11b) groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-2R^(g);

R¹² is, independently at each occurrence, H, F, or C₁₋₄ alkyl;

R¹³ is, independently at each occurrence, H, C₁₋₆ alkyl,—(CH₂)_(n)-phenyl, —(CH₂)_(n)-(5-10 membered heteroaryl), —C(O)R^(c),—C(O)OR^(c), —CONR⁸R^(c), —OCONR⁸R^(c), —S(O)₂R^(c), —C(O)O—(C₁₋₄alkyl)-OC(O)—(C₁₋₄ alkyl), or —C(O)O—(C₁₋₄ alkyl)-OC(O)—(C₆₋₁₀ aryl);wherein the said alkyl, phenyl, heteroaryl, aryl are optionallysubstituted with 0-2 R^(f);

R¹⁴ and R¹⁵ are, independently at each occurrence, H, F, or C₁₋₄ alkyl;

-   -   alternately, R¹⁴ combines with R¹⁵ to form ═O;

R^(a) is, independently at each occurrence, H, CF₃, C₁₋₆ alkyl,—(CH₂)_(r)—C₃₋₇ cycloalkyl, —(CH₂)_(r)—C₆₋₁₀ aryl, or —(CH₂)_(r)-5- to10 membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p); wherein said cycloalkyl, aryl andheteroaryl groups are optionally substituted with 0-2 R^(f);

R^(b) is, independently at each occurrence, CF₃, OH, C₁₋₄ alkoxy, C₁₋₆alkyl, —(CH₂)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d);

R^(c) is, independently at each occurrence, CF₃, C₁₋₆ alkyl substitutedwith 0-2 R^(f), C₃₋₆ cycloalkyl substituted with 0-2 R^(f), C₆₋₁₀ aryl,5- to 10-membered heteroaryl, (C₆₋₁₀ aryl)-C₁₋₄ alkyl, or (5- to10-membered heteroaryl)-C₁₋₄ alkyl, wherein said aryl and heteroarylgroups are optionally substituted with 0-3 R^(f);

R^(d) is, independently at each occurrence, H, ═O, ═NR⁸, OR^(a), F, Cl,Br, I, CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁸C(O)R^(a), —C(O)NR⁷R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl,—NR⁸SO₂CF₃, —NR⁸SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl,—S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e),C₂₋₆ alkenyl substituted with 0-2 R^(e), or C₂₋₆ alkynyl substitutedwith 0-2 R^(e);

R^(e) is, independently at each occurrence, ═O, OR^(a), F, Cl, Br, I,CN, NO₂, —NR⁸R⁹, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁸C(O)R^(a),—C(O)NR⁷R⁸, —SO₂NR⁸R⁹, NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl, —NR⁸SO₂CF₃,—NR⁸SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, or—(CF₂)_(r)CF₃;

R^(f) is, independently at each occurrence, H, ═O, —(CH₂)_(r)—OR^(g), F,Cl, Br, I, CN, NO₂, —NR^(9a)R^(9a), —C(O)R^(g), —C(O)OR^(g),—NR^(9a)C(O)R^(g), —C(O)NR^(9a)R^(9a), —SO₂NR^(9a)R^(9a),—NR^(9a)SO₂NR^(9a)R^(9a), —NR^(9a)SO₂—C₁₋₄ alkyl, —NR^(9a)SO₂CF₃,—NR^(9a)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl,—(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, or—(CH₂)_(r)-phenyl;

R^(g) is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl;

n, at each occurrence, is selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is selected from 0, 1, and 2;

r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and

s, at each occurrence, is selected from 1, 2, 3, and 4.

In a thirty-third aspect, the present invention provides a method fortreating a thromboembolic or an inflammatory disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of at least one compound of Formula (V), within the scope of thethirty-second aspect wherein:

A is C₃₋₈ cycloalkyl substituted with 0-1 R¹ and 0-3 R², C₄₋₈cycloalkenyl substituted with 0-1 R¹ and 0-3 R², phenyl substituted with0-1 R¹ and 0-3 R², naphthyl substituted with 0-1 R¹ and 0-3 R², or a 5-to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-1 R¹ and 0-3 R²;

Z is —C(R¹¹)(R¹²)—;

L is —C(O)NR¹⁰—, —NR¹⁰C(O)—, —CH₂C(O)NR¹⁰—, —CH₂NR¹⁰C(O)—,—C(O)NR¹⁰CH₂—, or —NR¹⁰C(O)CH₂—;

R³ is, independently at each occurrence, F, Cl, Br, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)C(O)NR⁸(CH₂)_(s)CO₂R^(3b), —(CH₂)_(r)CO₂R^(3b),—(CH₂)_(r)—C₃₋₈ cycloalkyl substituted with 0-2 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-phenyl substituted with 0-3 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-naphthyl substituted with 0-3 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-indanyl substituted with 0-3 R^(3a) and 0-1 R^(3d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(3a) and 0-1 R^(3d);

R⁴ is H, F, Cl, Br, I, OCF₃, CF₃, OR^(a), SR^(a), CN, NO₂, —C(O)R^(a),—C(O)OR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with0-2 R^(4a), C₂₋₆ alkenyl substituted with 0-2 R^(4a), C₂₋₆ alkynylsubstituted with 0-2 R^(4a), phenyl substituted with 0-2 R^(4b), or a5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(4b);

R⁶ is, independently at each occurrence, H, C₁₋₆ alkyl —CH₂OR^(a),—C(O)R^(c), —C(O)₂R^(c), or —(CH₂)_(r)-phenyl substituted with 0-3R^(d);

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-3 R^(10a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d); and

R¹¹ is C₁₋₄ haloalkyl, —(CH₂)_(r)C(O)NR⁸R⁹, C₁₋₆ alkyl substituted with0-3 R^(11a), C₂₋₆ alkenyl substituted with 0-3 R^(11a), C₂₋₆ alkynylsubstituted with 0-3 R^(11a), —(CH₂)—C₃₋₁₀ carbocycle substituted with0-3 R^(11b), or —(CH₂)_(r)-5-10 membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(11b).

In a thirty-fourth aspect, the present invention provides a method fortreating a thromboembolic or an inflammatory disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of at least one compound of Formula (V), within the scope of thethirty-second aspect wherein:

A is C₅₋₆ cycloalkyl substituted with 0-1 R¹ and 0-2 R², C₅₋₆cycloalkenyl substituted with 0-1 R¹ and 0-2 R², phenyl substituted with0-1 R¹ and 0-3 R², naphthyl substituted with 0-1 R¹ and 0-3 R², or a 5-to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-1 R¹ and 0-3 R²;

R³ is, independently at each occurrence, F, Cl, Br, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)C(O)NR⁸(CH₂)_(s)CO₂R^(3b), —(CH₂)_(r)CO₂R^(3b),—(CH₂)_(r)-phenyl substituted with 0-3 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-naphthyl substituted with 0-3 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-indanyl substituted with 0-3 R^(3a) and 0-1 R^(3d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(3a) and 0-1 R^(3d); and

R⁶ is, independently at each occurrence, H or C₁₋₆ alkyl.

In a thirty-fifth aspect, the present invention provides a method fortreating a thromboembolic or an inflammatory disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of at least one compound of Formula (V), within the scope of thethirty-second aspect wherein:

the group

is selected from:

In a thirty-sixth aspect, the present invention provides a method fortreating a thromboembolic or an inflammatory disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of at least one compound of Formula (V), within the scope of thethirty-second aspect wherein:

the group

is selected from:

In a thirty-seventh aspect, the present invention provides a method fortreating a thromboembolic or an inflammatory disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of at least one compound of Formula (III), within the scope ofthe thirty-second aspect wherein:

A is substituted with 0-1 R¹ and 0-2 R² and selected from: C₃₋₇cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, pyridyl,indazolyl, benzimidazolyl, benzisoxazolyl, isoquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,quinazolinyl, 1H-quinazolin-4-onyl, 2H-isoquinolin-1-onyl,3H-quinazolin-4-onyl, 3,4-dihydro-2H-isoquinolin-1-onyl,2,3-dihydroisoindolinonyl, and phthalazinyl;

the group

is selected from:

Z is —CH(R¹²)—;

L is —C(O)NR¹⁰—, —NR¹⁰C(O)—, —CH₂C(O)NR¹⁰—, —CH₂NR¹⁰C(O)—,—C(O)NR¹⁰CH₂—, or —NR¹⁰C(O)CH₂—;

R³ is, independently at each occurrence, F, Cl, Br, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)C(O)NR⁸(CH₂)_(s)CO₂R^(3b), —(CH₂)_(r)-phenyl substituted with0-3 R^(3a) and 0-1 R^(3d), —(CH₂)_(r)-naphthyl substituted with 0-3R^(3a) and 0-1 R^(3d), —(CH₂)_(r)-indanyl substituted with 0-3 R^(3a)and 0-1 R^(3d) or —(CH₂)_(r)-5-10 membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p), andsubstituted with 0-3 R^(3a) and 0-1 R^(3d);

R⁴ is, independently at each occurrence, H, ═O, F, Cl, Br, I, OCF₃, CF₃,CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkylsubstituted with 0-2 R^(4a), C₂₋₆ alkenyl substituted with 0-2 R^(4a),C₂₋₆ alkynyl substituted with 0-2 R^(4a), phenyl substituted with 0-2R^(4b), or a 5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), and substituted with 0-3R^(4b);

R⁶ is H, C₁₋₆ alkyl, or —(CH₂)_(r)-phenyl substituted with 0-3 R^(d);

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-2 R^(10a), —(CH₂)_(r)-phenyl substituted with 0-2 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(d); and

R¹² is, independently at each occurrence, H, F, or Me.

In another aspect, the present invention provides a method for treatinga thromboembolic or an inflammatory disorder, comprising: administeringto a patient in need thereof a therapeutically effective amount of atleast one compound of Formula (III), within the scope of thetwenty-eighth aspect wherein:

the group

In another aspect, L is —C(O)NR¹⁰— or —NR¹⁰C(O)—.

In another aspect, L is —C(O)NR¹⁰—.

In another aspect, L is —NR¹⁰C(O)—.

In another aspect, L is —C(O)NH— or —NHC(O)—.

In another aspect, L is —C(O)NH—.

In another aspect, L is —NHC(O)—.

In another aspect, the present invention provides a compound selectedfrom the exemplified examples or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

In another embodiment, the present invention provides a novelpharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention or a stereoisomer, tautomer, a pharmaceuticallyacceptable salt, solvate or prodrug form thereof.

In another embodiment, the present invention provides a novel processfor making a compound of the present invention or a stereoisomer,tautomer, pharmaceutically acceptable salt, solvate or prodrug formthereof.

In another embodiment, the present invention provides a novelintermediate for making a compound of the present invention or astereoisomer, tautomer, pharmaceutically acceptable salt, solvate orprodrug form thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom potassium channel openers, calcium channel blockers, sodiumhydrogen exchanger inhibitors, antiarrhythmic agents,antiatherosclerotic agents, anticoagulants, antithrombotic agents,prothrombolytic agents, fibrinogen antagonists, diuretics,antihypertensive agents, ATPase inhibitors, mineralocorticoid receptorantagonists, phospodiesterase inhibitors, antidiabetic agents,anti-inflammatory agents, antioxidants, angiogenesis modulators,antiosteoporosis agents, hormone replacement therapies, hormone receptormodulators, oral contraceptives, antiobesity agents, antidepressants,antianxiety agents, antipsychotic agents, antiproliferative agents,antitumor agents, antiulcer and gastroesophageal reflux disease agents,growth hormone agents and/or growth hormone secretagogues, thyroidmimetics, anti-infective agents, antiviral agents, antibacterial agents,antifungal agents, cholesterol/lipid lowering agents and lipid profiletherapies, and agents that mimic ischemic preconditioning and/ormyocardial stunning, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom an antiarrhythmic agent, an anti-hypertensive agent, ananti-coagulant agent, an anti-platelet agent, a thrombin inhibitingagent, a thrombolytic agent, a fibrinolytic agent, a calcium channelblocker, a cholesterol/lipid lowering agent, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom warfarin, unfractionated heparin, low molecular weight heparin,synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen,naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam,diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel,tirofiban, eptifibatide, abciximab, melagatran, ximelagatran,disulfatohirudin, tissue plasminogen activator, modified tissueplasminogen activator, anistreplase, urokinase, and streptokinase, or acombination thereof.

In a preferred embodiment, the present invention provides apharmaceutical composition wherein the additional therapeutic agent isan antihypertensive agent selected from ACE inhibitors, AT-1 receptorantagonists, ET receptor antagonists, dual ET/AII receptor antagonists,and vasopepsidase inhibitors, an antiarrythmic agent selected fromI_(Kur) inhibitors, or an antithrombotic agent selected fromanticoagulants selected from thrombin inhibitors, other factor XIainhibitors, other kallikrein inhibitors, factor VIIa inhibitors andfactor Xa inhibitors, and antiplatelet agents selected from GPIIb/IIIablockers, P2Y₁ and P2Y₁₂ antagonists, thromboxane receptor antagonists,and aspirin, or a combination thereof.

In a preferred embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof.

In a preferred embodiment, the present invention provides apharmaceutical composition, wherein the additional therapeutic agent isthe anti-platelet agent clopidogrel.

In another embodiment the present invention provides a method formodulation of the coagulation cascade and/or contact activation systemcomprising administering to a patient in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, tautomer, a pharmaceuticallyacceptable salt, solvate or prodrug form thereof.

In another embodiment, the present invention provides a novel method fortreating thromboembolic disorders comprising: administering to a patientin need of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a stereoisomer,tautomer, a pharmaceutically acceptable salt, solvate or prodrug formthereof.

In another embodiment, the present invention provides a novel method,wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, arterial cerebrovascularthromboembolic disorders, and venous cerebrovascular thromboembolicdisorders.

In another embodiment, the present invention provides a novel method,wherein the thromboembolic disorder is selected unstable angina, anacute coronary syndrome, atrial fibrillation, first myocardialinfarction, recurrent myocardial infarction, ischemic sudden death,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from (a) prosthetic valvesor other implants, (b) indwelling catheters, (c) stents, (d)cardiopulmonary bypass, (e) hemodialysis, and (f) other procedures inwhich blood is exposed to an artificial surface that promotesthrombosis.

In another embodiment, the present invention provides a method fortreating inflammatory disorders comprising: administering to a patientin need of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a stereoisomer,tautomer, a pharmaceutically acceptable salt, solvate or prodrug formthereof.

In another embodiment, the present invention provides a method, whereinthe inflammatory disorder is selected from the group consisting ofsepsis, acute respiratory dystress syndrome, and systemic inflammatoryresponse syndrome.

In another embodiment, the present invention provides a novel method oftreating a patient in need of thromboembolic disorder treatment,comprising: administering a compound of the present invention or astereoisomer, tautomer, a pharmaceutically acceptable salt, solvate orprodrug form thereof in an amount effective to treat a thromboembolicdisorder.

In another embodiment, the present invention provides a method oftreating a patient in need of inflammatory disorder treatment,comprising: administering a compound of the present invention or astereoisomer, tautomer, a pharmaceutically acceptable salt, solvate orprodrug form thereof in an amount effective to treat an inflammatorydisorder.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising:

(a) a first container;

(b) a pharmaceutical composition located within the first container,wherein the composition, comprises: a first therapeutic agent,comprising: a compound of the present invention or a stereoisomer,tautomer, a pharmaceutically acceptable salt, solvate or prodrug formthereof and

(c) a package insert stating that the pharmaceutical composition can beused for the treatment of a thromboembolic and/or inflammatory disorder.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising:

(d) a second container;

wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising:

(a) a first container;

(b) a pharmaceutical composition located within the first container,wherein the composition, comprises: a first therapeutic agent,comprising: a compound of the present invention or a stereoisomer,tautomer, a pharmaceutically acceptable salt, solvate or prodrug formthereof; and

(c) a package insert stating that the pharmaceutical composition can beused in combination with a second therapeutic agent to treat athromboembolic and/or inflammatory disorder.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising:

(d) a second container;

wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.

In another embodiment, the present invention provides a novel method,comprising: administering a compound of the present invention or astereoisomer, tautomer, a pharmaceutically acceptable salt, solvate orprodrug form thereof in an amount effective to treat a thromboembolicand/or inflammatory disorder.

In another embodiment, the present invention provides a compound of thepresent invention or a stereoisomer, tautomer, a pharmaceuticallyacceptable salt, solvate or prodrug form thereof, for use in therapy.

In another embodiment, the present invention also provides the use of acompound of the present invention or a stereoisomer, tautomer, apharmaceutically acceptable salt, solvate or prodrug form thereof, forthe manufacture of a medicament for the treatment of a thromboembolicand/or inflammatory disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional more preferredembodiments. It is also to be understood that each individual element ofthe preferred embodiments is its own independent preferred embodiment.Furthermore, any element of an embodiment is meant to be combined withany and all other elements from any embodiment to describe an additionalembodiment.

DEFINITIONS

Compounds of this invention may have one or more asymmetric centers.Unless otherwise indicated, all chiral (enantiomeric and diastereomeric)and racemic forms of compounds of the present invention are included inthe present invention. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds, and all suchstable isomers are contemplated in the present invention. Accordingly,the present compounds can be isolated in optically active or racemicforms. It is well known in the art how to prepare optically activeforms, such as by resolution of racemic forms or by synthesis fromoptically active starting materials. All chiral, (enantiomeric anddiastereomeric) and racemic forms and all geometric isomeric forms of astructure are intended, unless the specific stereochemistry or isomerform is specifically indicated. All tautomers of shown or describedcompounds are also considered to be part of the present invention.

Preferably, the molecular weight of compounds of the present inventionis less than about 500, 550, 600, 650, 700, 750, or 800 grams per mole.Preferably, the molecular weight is less than about 800 grams per mole.More preferably, the molecular weight is less than about 750 grams permole. Even more preferably, the molecular weight is less than about 700grams per mole.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁-C₁₀ alkyl”or “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂, C₃, C₄,C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, for example,“C₁₋₆ alkyl” denotes alkyl having 1 to 6 carbon atoms. Alkyl groups canbe unsubstituted or substituted so that one or more of its hydrogens arereplaced by another chemical group. Example alkyl groups include, butare not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more doublecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkenyl” (or alkenylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkenyl groups. Examples of alkenyl include, but arenot limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl,2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more triplecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkynyl” (or alkynylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkynyl groups; such as ethynyl, propynyl, butynyl,pentynyl, hexynyl and the like.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” refers to branched and straight-chained, having one or morehalogen substituents. Example haloalkyl groups include, but are notlimited to, CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂C₅, and the like.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁₋₆alkoxy” (or alkyloxy), is intended to include C₁, C₂, C₃, C₄, C₅, and C₆alkoxy groups. Example alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy,and the like. Similarly, “alkylthio” or “thioalkoxy” represents an alkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example methyl-S—, ethyl-S—, andthe like.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluorothoxy, and the like. Similarly,“haloalkylthio” or “thiohaloalkoxy” represents a haloalkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge; for example trifluoromethyl-S—, pentafluoroethyl-S—,and the like.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. C₃₋₇ cycloalkyl is intended to includeC₃, C₄, C₅, C₆, and C₇ cycloalkyl groups. Example cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring,any of which may be saturated, partially unsaturated, unsaturated oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, andtetrahydronaphthyl (tetralin). As shown above, bridged rings are alsoincluded in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).Preferred carbocycles, unless otherwise specified, are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term“carbocycle” is used, it is intended to include “aryl”. A bridged ringoccurs when one or more carbon atoms link two non-adjacent carbon atoms.Preferred bridges are one or two carbon atoms. It is noted that a bridgealways converts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, phenanthranyl, and the like.Aryl moieties are well known and described, for example, in Lewis, R.J., ed., Hawley's Condensed Chemical Dictionary, 13th Edition, JohnWiley & Sons, Inc., New York (1997). Aryl groups can be substituted orunsubstituted.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 5-, 6-, or 7-membered monocyclic or bicyclicor 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered bicyclic heterocyclicring which is saturated, partially unsaturated or fully unsaturated, andwhich consists of carbon atoms and 1, 2, 3 or 4 heteroatomsindependently selected from N, O and S; and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized (i.e., N→O and S(O)_(p)). The nitrogen atom may be substitutedor unsubstituted (i.e., N or NR wherein R is H or another substituent,if defined). The heterocyclic ring may be attached to its pendant groupat any heteroatom or carbon atom that results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. A nitrogen in theheterocycle may optionally be quaternized. It is preferred that when thetotal number of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl,2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

Preferred 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxazolidinyl,tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl,triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl,benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl,benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl,isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl,isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl,imidazolopyridinyl, and pyrazolopyridinyl.

Preferred 5- to 6-membered heterocycles include, but are not limited to,pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxazolidinyl,tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, andtriazolyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean a stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, benzodioxane, and the like. Heteroaryl groups can besubstituted or unsubstituted. The nitrogen atom may be substituted orunsubstituted (i.e., N or NR wherein R is H or another substituent, ifdefined). The nitrogen and sulfur heteroatoms may optionally be oxidized(i.e., N→O and S(O)_(p)). It is to be noted that total number of S and Oatoms in the aromatic heterocycle is not more than 1. Bridged rings arealso included in the definition of heterocycle. A bridged ring occurswhen one or more atoms (i.e., C, O, N, or S) link two non-adjacentcarbon or nitrogen atoms. Preferred bridges include, but are not limitedto, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogenatoms, and a carbon-nitrogen group. It is noted that a bridge alwaysconverts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge.

The term “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As referred to herein, the term “substituted” means that one or morehydrogen atoms is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering.

When any variable (e.g., R^(2a), R^(2b), etc.) occurs more than one timein any constituent or formula for a compound, its definition at eachoccurrence is independent of its definition at every other occurrence.Thus, for example, if a group is shown to be substituted with 0-3R^(2b), then said group may optionally be substituted with up to threeR^(2b) groups and R^(2b) at each occurrence is selected independentlyfrom the definition of R^(2b). Also, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a dotted ring is used within a 5- to 8-membered ring structure,this indicates that the ring structure may be saturated, partiallysaturated or unsaturated.

As used herein, the term “protecting group” for amines means any groupknown in the art of organic synthesis for the protection of amine groupswhich is stable to an ester reducing agent, a disubstituted hydrazine,R4-M and R7-M, a nucleophile, a hydrazine reducing agent, an activator,a strong base, a hindered amine base and a cyclizing agent. Such amineprotecting groups fitting these criteria include those listed in Greeneet al., Protective Groups in Organic Synthesis, John Wiley & Sons, NewYork (1991) and The Peptides: Analysis, Synthesis, Biology, Vol. 3,Academic Press, New York (1981), the disclosure of which is herebyincorporated by reference. Examples of amine protecting groups include,but are not limited to, the following: (Fmoc); (1) acyl types such asformyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromaticcarbamate types such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;(5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanesuch as trimethylsilane; (7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such astriphenylmethyl, methyl, and benzyl; and substituted alkyl types such as2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilanetypes such as trimethylsilane.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The term “pharmaceutically acceptable salt” refers to acid or base saltsof the compounds described herein. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Pharmaceuticallyacceptable salts of the compounds of the invention can be prepared byreacting the free acid or base forms of these compounds with astoichiometric amount of the appropriate base or acid in water or in anorganic solvent, or in a mixture of the two; generally, nonaqueous medialike ether, ethyl acetate, ethanol, isopropanol, or acetonitrile arepreferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th Edition, p. 1418, Mack Publishing Company,Easton, Pa. (1985), the disclosure of which is hereby incorporated byreference in its entirety. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. Pharmaceutically acceptable saltsinclude the conventional non-toxic salts or the quaternary ammoniumsalts of the parent compound formed, for example, from non-toxicinorganic or organic acids. Such conventional non-toxic salts includethose derived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric, and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   -   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985);    -   b) Widder, K. et al., eds., Methods in Enzymology, 112:309-396,        Academic    -   Press (1985);    -   c) Bundgaard, H., Chapter 5: “Design and Application of        Prodrugs”, A Textbook of Drug Design and Development, pp.        113-191, Krogsgaard-Larsen, P. et al., eds., Harwood Academic        Publishers (1991);    -   d) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);    -   e) Nielsen, N. M. et al., J. Pharm. Sci., 77:285 (1988); and    -   f) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (1994), which isincorporated herein by reference in its entirety.

Radiolabelled compounds of the present invention, i.e., wherein one ormore of the atoms described are replaced by a radioactive isotope ofthat atom (e.g., C replaced by ¹³C or by ¹⁴C; and isotopes of hydrogeninclude tritium and deuterium), are also provided herein. Such compoundshave a variety of potential uses, e.g., as standards and reagents indetermining the ability of a potential pharmaceutical to bind to targetproteins or receptors, or for imaging compounds of this invention boundto biological receptors in vivo or in vitro.

Compounds of the present invention are, subsequent to their preparation,preferably isolated and purified to obtain a composition containing anamount by weight equal to or greater than 98%, preferably 99%, compoundof the present invention (“substantially pure”), which is then used orformulated as described herein. Such “substantially pure” compounds arealso contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

It should further be understood that solvates (e.g., hydrates) of thecompounds of the present invention are also with the scope of thepresent invention. Methods of solvation are generally known in the art.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit factor XIa and/or plasma kallikrein.“Therapeutically effective amount” is also intended to include an amountof the combination of compounds claimed that is effective to inhibitfactor XIa and/or plasma kallikrein. The combination of compounds ispreferably a synergistic combination. Synergy, as described, forexample, by Chou et al., Adv. Enzyme Regul., 22:27-55 (1984), occurswhen the effect (in this case, inhibition of factor XIa and/or plasmakallikrein) of the compounds when administered in combination is greaterthan the additive effect of the compounds when administered alone as asingle agent. In general, a synergistic effect is most clearlydemonstrated at suboptimal concentrations of the compounds. Synergy canbe in terms of lower cytotoxicity, increased antithrombotic and/oranti-inflammatory effect, or some other beneficial effect of thecombination compared with the individual components.

The present invention further includes compositions comprising one ormore compounds of the present invention and a pharmaceuticallyacceptable carrier. A “pharmaceutically acceptable carrier” refers tomedia generally accepted in the art for the delivery of biologicallyactive agents to animals, in particular, mammals. Pharmaceuticallyacceptable carriers are formulated according to a number of factors wellwithin the purview of those of ordinary skill in the art. These include,without limitation: the type and nature of the active agent beingformulated; the subject to which the agent-containing composition is tobe administered; the intended route of administration of thecomposition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Remington's Pharmaceutical Sciences, 17th Edition, MackPublishing Company, Easton, Pa. (1985), which is incorporated herein byreference in its entirety.

SYNTHESIS

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. Also, in the descriptionof the synthetic methods described below, it is to be understood thatall proposed reaction conditions, including choice of solvent, reactionatmosphere, reaction temperature, duration of the experiment and workupprocedures, are chosen to be the conditions standard for that reaction,which should be readily recognized by one skilled in the art. It isunderstood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reactions proposed. Such restrictionsto the substituents that are compatible with the reaction conditionswill be readily apparent to one skilled in the art and alternate methodsmust then be used.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group(s) (PG) used for protection of the reactivefunctional groups present in the compounds described in this invention.An authoritative account describing the many alternatives to the trainedpractitioner is Greene et al. (Protective Groups In Organic Synthesis,Third Edition, Wiley-Interscience, (1999)).

All references cited herein are hereby incorporated in their entiretyherein by reference.

Imidazole compounds useful for the synthesis of the compounds of thisinvention may be synthesized according to the general method outlined inScheme 1 (Con tour-Galcera et al., Bioorg. Med. Chem. Lett.,11(5):741-745 (2001)). An appropriately protected or derivatized alphaamino acid [1; Y=R¹⁰(PG)N— or Y=AC(O)N(R¹⁰-] or malonic acid derivative[1; Y=alkyl-OC(O)—] is dissolved in an suitable solvent, such asethanol/water (1:1), and treated with a base, such as cesium carbonate,to form the cesium salt. The salt is isolated and re-suspended in asuitable solvent, such as dimethyl formamide, and combined with analpha-bromoketone 2 to form the keto ester 3. Alternatively, formationof keto ester 3 (X=aryl or heteroaryl) may be carried out in a singlereaction vessel by forming the cesium salt of 1 in the same solvent(e.g., dimethyl formamide) used for the alkylation step.

The imidazole having structure 4 is formed by heating the keto ester 3to reflux in a suitable solvent, such as xylenes, in the presence ofexcess ammonium acetate using a Dean-Stark trap to remove water.Formation of the imidazole can also be carried out by combining the ketoester 3 and ammonium acetate in a suitable solvent, such as xylene orethanol or a combination of solvents such as dimethylforamide andethanol (1:1), using microwave heating. When Y=R¹⁰(PG)N—, the protectinggroup on the amine is removed in preparation for acylation of the amine,which is outlined in Scheme 18. For example, when the protecting groupis a BOC moiety, the amine is de-protected with strong acid, such astrifluoroacetic acid in suitable solvent, such as dichloromethane, togive compound 5, where Y′=R¹⁰HN—. When Y=Alk-OCO—, the ester may behydrolyzed by dissolving it in a suitable solvent such as methanol andtreating the ester with a base such as aqueous sodium hydroxide to give5 where Y=—CO₂H.

Further functional group incorporation on to the imidazole ring may beachieved by bromination of the C-5 carbon of the imidazole ring using,for example, bromine or N-bromosuccinimide, in a suitable solvent suchas methylene chloride or chloroform to give compounds 6 and 9.Alternatively, the C-5 carbon may be chlorinated with, for example,N-chlorosuccinimide, using a suitable solvent such as methylenechloride, acetonitrile or chloroform to give compounds 7 and 10.

The brominated imidazoles 6 and 9 provide suitable functionality forfurther elaboration using a wide variety of palladium catalyzed crosscoupling procedures known to those skilled in the art such as describedby Tsuji (Palladium Reagents and Catalysts: New Perspectives for the21st Century, John Wiley & Sons, Ltd. (2004)). By way of example,application of a Suzuki coupling protocol using a modified method ofZhong et al. (Org. Lett., 6:929-931 (2004)) and Bellina et al.(Synthesis, 15:2419-2440 (2004)), where the bromides 6 or 9 are combinedwith a boronic acid in the presence of a base, typically tribasicpotassium phosphate or sodium carbonate, and a palladium catalyst,typically bis-(tri-t-butylphosphine) palladium (0),tris-(dibenzylidene-acetone) palladium (0), ortetrakis-(triphenylphosphine) palladium (0), in a suitable solvent, suchas toluene or 1,4-dioxane heated to between 80-110° C. usingconventional or microwave heating, provides structures 8 and 11, whereX=aryl or heteroaryl.

An alternate synthesis of the imidazole core is shown in Scheme 2. Asuitably protected beta amino aldehyde 12, glyoxal trimeric dihydrate 13and ammonia are combined in a suitable solvent such as methanol andstirred together at room temperature. The resulting imidazole 14 isdissolved in a suitable solvent such as chloroform and brominated using,for example, N-bromosuccinimide. Other brominating reagents may beemployed, such as bromine, and other solvents suitable for brominationconditions, such as methylene chloride or carbon tetrachloride, may beused. The 4,5-dibromo imidazole 15 is treated with a reducing agent suchas sodium hydrogen sulfite utilizing a biphasic solvent systemconsisting of, for example, 1,4-dioxane and water, and a phase transfercatalyst such as tetrabutylammonium hydrogen sulfate. The mono-bromide16 thus produced may be combined with a suitably functionalized arylboronic acid or heteroaryl boronic acid in a suitable solvent such as1,4-dioxane or toluene, and treated at elevated temperature with areagent combination consisting of, for example, palladium (I)tri-tert-butylphosphine bromide dimer and tribasic potassium phosphateaccording to a modified procedure of Zhong et al. and Bellini et al.referenced previously. Other reagent combinations that may be utilizedfor the Suzuki coupling procedure are palladiumtris-(dibenzylidene-acetone) palladium (0), tri-(tert-butyl)-phosphoniumtetra-fluoroborate, and tribasic potassium phosphate. The protectinggroup on the amine is removed in preparation for acylation of the amine,which is outlined in Scheme 17. For example, when the protecting groupis a BOC moiety, the amine is de-protected with strong acid, such astrifluoroacetic acid, in suitable solvent, such as dichloromethane, togive amine 18 as the bis-TFA salt.

Another alternative method for the synthesis of the imidazole ring isshown in Scheme 3. 3,3-Dibromo-1,1,1-trifluoropropan-2-one (19) iscombined with ammonium acetate in a suitable solvent such as water andheated to 90° C., followed by the addition of a suitably protectedaldehyde 12. The trifluoromethyl imidazole thus produced provides anintermediate for the synthesis of C-5 trifluoro methyl analogsillustrated by compound 24, where X=CF₃. Such compounds may be accessedby methods previously illustrated in Schemes 1 and 2. Alternatively, thetrifluoromethyl moiety may be hydrolyzed under strongly basic conditionsusing, for example sodium methoxide, to provide the ortho ester which ishydrolyzed to the methyl ester 21, where X═—CO₂CH₃. This intermediatemay be utilized using procedures already illustrated in Schemes 1 and 2to access compounds such as 24, where X═—CO₂CH₃.

Phenylalanine analogs bearing substituents on the phenyl ring notcommercially available are readily accessed using methods known to thoseskilled in the art. For an authoritative review of methods for thesynthesis of such analogs starting from glycine see Maruoka et al.(Chem. Rev., 103:3013-3028 (2003)).

Certain 2-bromoacetophenone analogs that are not commercially availablemay be synthesized from commercially available starting materials. Forexample, ethyl 2-(4-(2-bromoacetyl)phenyl)acetate (27: R^(3a)═R^(3b)═H)can be prepared as shown in Scheme 4. 2,4′-dibromoacetophenone (25:R^(3a)═R^(3b)═H), and ethyl bromoacetate (26) are dissolved in asuitable solvent, such as tetrahydrofuran, and treated at elevatedtemperature with a combination of reagents, such as palladium (II)acetate, tris-(1-naphthyl)phosphine and tri-basic potassium phosphateaccording to the method of Gossen et al. (Chem. Commun., 669-670(2001)). The intermediate, ethyl 2-(4-acetylphenyl)acetate (27) isbrominated by dissolving in a suitable solvent such as chloroform andtreating with a brominating reagent such as bromine to give ethyl2-(4-(2-bromoacetyl)phenyl)acetate (28). This reaction sequence may alsobe employed to prepare the other regioisomers and analogs of 28containing functional groups compatible with the reaction sequencedescribed.

Certain functional groups present in the final structures must, byvirtue of incompatibility with the formation of the imidazole shown inSchemes 1-3, be incorporated into the structure after the imidazole ringhas been formed. Examples of such functional groups include, but are notlimited to, carbamoyl, aminoindazolyl, aminobenzisoxazolyl, andaminoquinazolinoyl (see Schemes 5 and 6).

The carbamoyl group, illustrated in structure 29 in Scheme 5, may beincorporated into the final structure by hydrolysis of a nitrile using,for example, potassium carbonate, hydrogen peroxide, and DMSO assolvent, according to the method of Katritzky et al. (Synthesis,12:949-950 (1989)). When the nitrile is located para to the imidazolering, magnesium oxide must be added to the reaction mixture. The amidinegroup, illustrated in structure 31, may be incorporated into the finalstructure via Pinner reaction followed by ammonolysis. Alternatively,the nitrile 28 may be combined with hydroxylamine hydrochloride in thepresence of a base, such as triethylamine, to give the amidoxime 32,which after acetylation with acetic anhydride is reduced by a variety ofmethods including, but not limited by, catalytic hydrogenation using,for example, palladium on carbon and hydrogen (Judkins et al., Synth.Comm., 26:4351-4367 (1996)), or by using an active metal such as zinc.By way of illustration, the precursor nitrile group shown in structure28 in Scheme 5 may be incorporated on to the intermediate structure(s)by using, in separate reactions, 4-(2-bromo-acetyl)-benzonitrile,3-(2-bromo-acetyl)-benzonitrile, or 2-(2-bromo-acetyl)-benzonitrile forthe reagent described as BrCH₂C(O)X in Scheme 1.

The aminoindazole, aminobenzisoxazole and aminoquinazoline functionalgroups may be incorporated into the final structure using a commonintermediate containing a phenyl ring bearing an ortho fluoro nitrile asillustrated in structure 33 (Scheme 6). The amino-indazole functionalgroup (34) is produced, for example, by heating 33 with hydrazinemonohydrate in a suitable solvent, such as n-butanol. Heating may bedone conventially or via microwave irradiation, and the temperaturerequired for conversion of the ortho fluoro nitrile to the aminoindazoledepends upon the regioisomeric relationship between the ortho fluoronitrile and the imidazole ring. Typically, temperatures of 160° C. arerequired for formation of the amino-indazole when the nitrile is locatedpara to the imidazole ring. The aminoquinazoline (35) is produced bycombining the ortho-fluoronitrile (33) with formamidine acetate, orother suitable salt forms, in a suitable solvent such as dimethylacetamide or dimethyl formamide, and heating to approximately 140° C.Conversion of the ortho-fluoronitrile to the aminobenzisoxazole (36) maybe accomplished by combining the fluoro nitrile 33 withacetoxyhydroxamic acid in the presence of a base such as potassiumcarbonate.

A general synthesis of alpha bromoketones containing an ortho fluoronitrile is illustrated in Scheme 7. A suitably substitutedbromo-fluoro-benzoic acid (37) is converted to the corresponding nitrile38 using, for example, zinc cyanide and palladium (0)tetrakis-(triphenylphosphine) in a suitable solvent, such as dimethylformamide, and heating to 90° C. The nitrile 38 thus produced is treatedsequentially with oxalyl chloride in a suitable solvent, such asdichloromethane, containing a few drops of DMF, then treated withtrimethylsilyldiazomethane in a suitable solvent or solvent combination,such as acetonitrile and hexane. The intermediate diazoketone isisolated and treated with hydrobromic acid and acetic acid to providethe alpha bromoketone 39.

Alternatively, the bromoketone 39 may be synthesized from a suitablysubstituted ortho fluoro nitrile containing a bromide (40 Scheme 8) bytreatment sequentially with tributyl-(1-methoxyvinyl) stannane and apalladium catalyst, such as bis-(triphenylphosphine)-dichloro-palladium(II), in a suitable solvent, such as toluene, and heated to reflux,followed by aqueous hydrochloric acid, typically at 5% (w/v)concentration. The resulting methyl ketone 41 is combined with brominein a suitable solvent, such as chloroform or methylene chloride, toproduce the bromoketone 39. Alternate synthetic routes to 39 other thanthose illustrated in Schemes 7 and 8 may be envisioned by one skilled inthe art depending on the regioisomers commercially available forpossible combinations of R^(3a) and R^(3b) contained on the carbocyclicring.

A different sequence of chemical transformations provides for thesynthesis of a second regioisomer of the imidazoles useful in thepreparation of compounds of this invention as shown in Scheme 9. Analpha-bromoketone 42 containing suitable substitution is combined withsodium formate in a suitable solvent, such as ethanol, and heated toreflux. The keto ester 43 thus formed is dissolved in a solvent, forexample ethanol, and combined with a suitably substituted amidine 44(X=aryl or heteroaryl) in the presence of a base, for example sodiumbicarbonate. The imidazole 45 thus formed has the oppositeregio-configuration compared to the imidazoles illustrated in Schemes1-3. Removal of the amine protecting group, PG, in preparation foracylation of the amino group is carried out as described previously togive the amino imidazole 46.

Benzimidazole compounds useful for preparing compounds of this inventioncan be synthesized according to the general procedure shown in Scheme10. A suitably protected amino acid and a suitably substituted phenyldiamine 22 are dissolved in a solvent, for example pyridine, and treatedwith an amide bond forming reagent, such as BOP-reagent. The reactionmixture is heated to 80° C. to effect ring closure to the benzimidazole23. The protecting group on the amine is removed as before inpreparation for acylation of the amine, as outlined below in Scheme 17.

A general procedure for the synthesis of oxazoles having substituents inthe 2- and 4-positions useful for the synthesis of compounds of thisinvention is shown in Scheme 6. A suitably protected amino acid 1 andbeta-keto amine 50 (X=aryl or heteroaryl) are dissolved in a suitablesolvent, for example pyridine, and treated with amide coupling reagent,for example BOP reagent, at room temperature. The keto amide 51 thusformed is dehydrated by dissolving in a suitable solvent such as DMF andtreating the solution with phosphorous oxychloride at elevatedtemperature (Sow et al., J. Org. Chem., 55:386 (1990)). The oxazole 52is deprotected in preparation for acylation of the amine 53, which isoutlined in Scheme 17.

Suitably functionalized triazoles useful for the synthesis of compoundsof this invention can be synthesized according to the procedure outlinedin Scheme 12. A suitably protected amino acid 1 and hydrazine aredissolved in a suitable solvent, such as pyridine, and treated with anamide bond forming reagent. The resulting hydrazoic acid 54 is condensedwith a suitably substituted imidate 55 (X=aryl or heteroaryl). When theimidate is in the form of a hydrochloride salt, addition of a base suchas triethylamine is required. Solvents such as acetonitrile may beemployed. The triazole 56 thus formed is deprotected to provide amine57, which is used in Scheme 17 below. For example, when the protectinggroup is a BOC moiety, the amine is de-protected with trifluoroaceticacid in dichloromethane to give amine 53 as the bis-TFA salt.

Suitably substituted pyrazoles useful for the synthesis of compounds ofthis invention may be synthesized using the procedures shown in Scheme13 (Ohta, S. et al., Chem. Pharm. Bull., 29(10):2762 (1981)). A suitablysubstituted β-keto ester 58 (X=aryl or heteroaryl) is dissolved in asuitable solvent and the ester hydrolyzed with, for example, sodiumhydroxide. The magnesium salt (60) of the beta keto acid 59 is formed bydissolving the acid in a suitable solvent such as methanol and THFfollowed by addition of magnesium ethoxide. In a separate reactionsequence, the carboxylic acid of a suitably protected amino acid 1(Y=R¹⁰N(PG)-) is activated with, for example, carbonyl diimidazole togive the activated amino acid 61 (LG=imidazol-1-yl in thisillustration). Compounds 60 and 61 are combined in a suitable solvent,for example DMF, to give the beta diketone 62. Treatment of 62 withhydrazine at elevated temperatures affords the pyrazole 63. When theamino group of 64 is protected with a CBz moiety, the protecting groupmay be removed by catalytic hydrogenation using, for example, palladiumon carbon and elemental hydrogen to give amine 64.

A general procedure for the formation of substituted triazolones usefulfor the synthesis of compounds of this invention is shown in Scheme 14.A suitably substituted protected beta-amino nitrile 65 is treated withthe sodium salt of an alcohol, for example sodium methoxide, to form theimidate 66. The imidate 66 is reacted with a suitably substitutedhydrazine 67 (X=aryl or heteroaryl) to form the amino amidine 68(Yanagisawa et al., J. Med. Chem., 27(7):849 (1984)). Treatment of 68with a bis-activated carbonyl such as carbonyl diimidazole(LG=imidazol-1-yl) provides the triazolone 69. Deprotection of the aminogroup of 69 is carried out in preparation for acylation of the nitrogen,which is outlined in Scheme 17. For example, when the amine is protectedwith a CBz moiety, the protecting group may be removed using catalytichydrogenation using, for example, palladium on carbon and hydrogen or,alternatively, by treatment with HBr in HOAC or neat TFA to give amine70.

The synthesis of imidazoles substituted with fused ring heterocycles inthe 4-position is shown in Scheme 15. A suitably protected andfunctionalized 4-trifluoromethyl imidazole 71 is available according tothe chemistry outlined in Scheme 3. The imidazole 71 is dissolved in asuitable solvent such as methanol and heated in the presence of a basesuch as sodium methoxide. The methyl ester 72 thus formed is dissolvedin a suitable solvent, for example, tetrahydrofuran, and combined withan aniline 47 substituted in the ortho position with either hydroxy,amino, mono alkyl amino or thiol. The aniline employed may haveadditional substituents, R^(3a) and R^(3e), known to those skilled inthe art to be compatible with the reaction conditions. The two reactantsare treated with a protic acid, for example, para-toluene sulfonic acid,to effect addition of the aniline and subsequent cyclization anddehydration to form the fused heterocycle 74. The amine protecting groupis removed in preparation for acylation of the amine, which is outlinedin Scheme 17. When the protecting group is a BOC moiety, the amine isde-protected with strong acid such as trifluoroacetic acid or HCl insuitable solvent such as dichloromethane or dioxane to give amine 75 asthe bis-TFA salt.

Thiazol-2-yl imidazole derivatives useful for the synthesis of compoundsof this invention can be prepared as shown in Scheme 16. A suitablysubstituted ester 76 and a beta amino thiol such as cysteine methylester 77 are combined in a suitable solvent such as tetrahydrofuran andtreated with a protic acid such as camphor sulfonic acid. Other betaamino thiols having functional groups compatible with these conditionsmay be employed in this reaction. The resulting thiazolidine 78 isoxidized to the thiazole 79 using, for example, manganese dioxide. Othersuitable oxidants may be employed in this step such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The amino group of 79 isdeprotected in preparation for acylation. For example, when theprotecting group is a BOC moiety, the amine is de-protected with strongacid such as trifluoroacetic acid in suitable solvent such asdichloromethane to give amine 80 as the bis-TFA salt.

Each of the aforementioned reaction Schemes 1-3 and 9-16 produce aheterocycle containing an aminoalkyl side chain suitable for reactingwith suitably substituted carboxylic acids, for example, N-Boctranexamic acid or 4-cyanobenzoic acid, under standard amide bondcoupling conditions (Scheme 17A). Reagent combinations commonly employedfor this transformation may be used and include, but are not limited to:BOP-reagent and pyridine; EDCI, HOAt, N-methyl morpholine; or EDCI,HOBt, N-methyl morpholine. Solvents suitable for this transformationinclude, but are not limited to, pyridine, THF and dimethylformamide.Solvent combinations may also be used such as dichloromethane and DMF inratios suitable to achieve solubility of the reagents employed.Alternately, the amines from Schemes 1-3 and 9-16 can be reacted withsuitable substituted alkylating agents or sulfonyl halides, usingmethods known to one skilled in the art. It should be recognized thatadditional deprotection steps and further functional group manipulationsof compounds obtained via Scheme 17 using methods known in the art willthen provide additional compounds of this invention.

Alternatively, when the heterocycle contains a aliphatic carboxylic acidcontaining side chain, amide bond formation may be effected by reactionwith a suitably substituted amine or aniline with the reagentcombinations described herein (Scheme 17B).

A suitably substituted carboxylic acid (A-CO₂H) is used in the amidecoupling shown in Scheme 17A. Many of these carboxylic acids arecommercially available. In case where the carboxylic acids are notcommercially available, they can be prepared from the correspondingbromide 87, alcohol 85, aldehyde 88, or ester 89 as shown in Scheme 18using methods known in the art. The R¹ and R² groups can be furthermanipulated using methods known in the art to provide additionalcompounds of this invention. For example, the cyano group can be used asR¹, which can be reduced to give CH₂NH₂ with a suitable reducing agentor converted to the amidine by reaction with hydroxylamine, and followedby palladium catalyzed hydrogenation using methods described previously.

When A is an isoquinoline moiety a modified procedure from U.S.Publication No. 2004/0077865 is followed. Heating the 2-methylbenzonitrile derivative 90 with1-(t-butoxy)-N,N,N′,N′-tetramethylmethanediamine in a suitable solventsuch as DMF gives the enamine 91. Condensation of enamine 91 and2,4-dimethoxybenzylamine in DMPU at elevated temperatures gives the1-imino-1,2-dihydroisoquinoline skeleton and subsequent hydrolysisprovides 92. Debenzylation of 92 with anisole in TFA at elevatedtemperatures provides 1-amino-isoquinoline 93. When A is a5,6,7,8-tetrahydroisoquinoline moiety a modified procedure of McEachernet al. is followed (J. Org. Chem., 67:7890 (2002)). Acid 92 is convertedto the ester 94. Debenzylation of 94 with anisole in TFA at elevatedtemperatures and acetylation with acetyl chloride and triethylamineyields 95. Hydrogenation over platinum oxide in the presence of TFAprovides the 1-amino-5,6,7,8-tetrahydroisoquinoline. Saponification ofthe ester with NaOH and hydrolysis of the amide under acidic conditionsgives 96.

When A is a 4-aminoquinazoline moiety, heating an appropriatelysubstituted ortho-fluoro benzonitrile 97 with formamidine acetate oracetamidine acetate in DMA, according to a modified procedure of Lam(Lam, P. Y. S. et al., J. Med. Chem., 46:4405 (2003)), gives4-aminoquinazoline 98 and 99. Saponification of the ester under basicconditions provides 100 and 101.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Solution ratio expresses a volume relationship, unless stated otherwise.NMR chemical shifts (δ) are reported in parts per million. Flashchromatography was carried out on silica gel according to Still's method(Still, W. C. et al., J. Org. Chem., 43:2923 (1978)).

As used throughout the specification, the following abbreviations forchemical reagents apply:

-   HOAc or AcOH=acetic acid-   Bn=benzyl-   Bu=butyl-   t-Bu=tertiary butyl-   Boc=tert-butyl oxycarbonyl-   BOP reagent=benzotriazol-1-yloxy-tris(dimethylamino)phosphonium    hexafluorophosphate-   Brine=saturated aqueous sodium chloride-   CSA=camphor sulfonic acid-   DMF=dimethylformamide-   DMSO=dimethyl sulfoxide-   EDCI=1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride-   Et=ethyl-   EtOH=ethanol-   EtOAc=ethyl acetate-   Me=methyl-   MeOH=methanol-   NaOAc=sodium actetate-   OAc=acetate-   Ph=phenyl-   Pr=propyl-   i-Pr=isopropyl-   i-PrOH=isopropanol-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   ° C.=degrees Celsius-   atm=atmosphere-   conc.=concentrated-   eq=equivalent(s)-   h or hr=hour(s)-   g=gram(s)-   mg=milligram(s)-   L=liter(s)-   mL=milliliter(s)-   μL=microliter(s)-   mmol=millimolar-   M=molar-   meq=milliequivalent(s)-   Min=minute(s)-   MW=molecular weight-   mp=melting point-   rt or RT=room temperature-   sat or sat'd=saturated-   ESI=electrospray ionization mass spectroscopy-   HPLC=high performance liquid chromatography-   MS=mass spectrometry-   LC/MS=liquid chromatography mass spectrometry-   HRMS=high resolution mass spectrometry-   NMR=nuclear magnetic resonance spectroscopy-   TLC=thin layer chromatography

“α”, “β”, “R”, “S”, “E”, and “Z” are stereochemical designationsfamiliar to one skilled in the art. One stereoisomer of a compound ofFormula I may display superior activity compared with the others. Thus,each stereoisomer of a compound of Formula I is considered to be a partof the present invention. When required, separation of the racemicmaterial can be achieved by HPLC using a chiral column or by aresolution using a resolving agent such as described in Wilen, S. H.,Tables of Resolving Agents and Optical Resolutions, 308 (1972) or usingenantiomerically pure acids and bases. A chiral compound of Formula Imay also be directly synthesized using a chiral catalyst or a chiralligand, e.g., Jacobsen, E., Acc. Chem. Res., 33:421-431 (2000) or usingother enantio- and diastereo-selective reactions and reagents known toone skilled in the art of asymmetric synthesis.

The following Examples have been prepared, isolated and characterizedusing the methods disclosed herein. The following Examples demonstrate apartial scope of the invention and are not meant to be limiting of thescope of the invention.

Example 1(S)-4-Carbamimidoyl-N-(2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethyl)benzamide,bistrifluoroacetic acid salt

Part A: (S)-tert-Butyl2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethylcarbamate

To a solution of L-N-(Boc)-phenylalanine (750 mg, 3.77 mmol) in EtOH/H₂O(1:1; 7.4 mL) was added with Cs₂CO₃ (650 mg, 1.89 mmol). The reactionwas stirred at rt for 1 h. The solvent was removed under vacuum and theresulting salt suspended in DMF (4.7 mL). 2-Bromoacetophenone (1.0 g,3.77 mmol) was added in a single portion and the reaction stirred at rtfor 1.5 h. The reaction was filtered to remove CsBr. The solids werewashed with DMF. The combined washings and filtrate were concentrated invacuo to yield a yellow solid (650 mg). The crude intermediate wasplaced in a flask fitted with a Dean-Stark trap and dissolved in xylenes(10 mL). NH₄OAc (2.64 g, 30 mmol) was added to the flask and thereaction was heated to reflux for 3 h. The reaction was cooled to rt andthe solvent removed in vacuo. The residue was redissolved in EtOAc andwashed with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄,filtered and evaporated to dryness to yield 780 mg of the desiredproduct (57% yield). MS 364.2 (M+H)⁺.

Alternatively, the keto ester intermediate and 10 equivalents of NH₄OAcwere dissolved in ethanol and heated to 160° C. in a sealed tube for 30min using microwave irradiation. The reaction was cooled to rt, theethanol was evaporated in vacuo and the residue was redissolved inEtOAc. The organic layer was washed with ½ saturated brine (2 times),dried over MgSO₄ and evaporated to dryness. The crude product thusformed was sufficiently pure to carry on to the next step.

Part B: (S)-2-Phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanaminebis-trifluoroacetic acid salt

The product from Example 1 Part A (100 mg, 0.28 mmol) was dissolved inCH₂Cl₂ (2.8 mL) and treated with neat TFA (0.2 mL, 10% v/v). Thereaction was stirred at rt for 16 h. The solvent and TFA were removed invacuo. The residue was redissolved in methanol. The solvent was removedin vacuo, the residue was re-dissolved in MeOH and the solvent wadevaporated in vacuo to yield 124 mg (92% yield) of crude amine as thebis-TFA salt. MS 262.2 (M−H)⁻.

Part C:(S)-4-Carbamimidoyl-N-(2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethyl)benzamide,bistrifluoroacetic acid salt

The product from Example 1 Part B (124 mg, 0.25 mmol) and4-amidinobenzoic acid hydrochloride (94 mg, 0.47 mmol) were dissolved inanhydrous pyridine (2 mL). BOP reagent (249 mg, 0.56 mmol) was added andthe reaction was stirred at rt for 16 h. The solvent was removed invacuo and the residue redissolved in MeOH/H₂O (9:1) containing 0.1% TFA.The solution was filtered and the title compound was isolated by prepHPLC to yield 9.2 mg of the desired product (3% yield). ¹H NMR (500 MHz,d₄-MeOH) δ 3.37 (dd, J=8.5 and 13 Hz, 1H), 3.46 (dd, J=8.5 and 13 Hz,1H), 5.48 (app t, J=8.2 Hz, 1H), 7.14-7.21 (m, 5H), 7.34-7.41 (m, 3H),7.56 (m, 2H), 7.68 (s, 1H), 7.80 (d, J=8.2 Hz), 7.96 (d, J=8.2 Hz, 2H):HRMS (M+H)⁺ for C₂₅H₂₃N₅O, calcd m/z: 410.1981, obs: 410.1974.

Example 2(S)-4-(Aminomethyl)-N-(2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethyl)cyclohexanecarboxamide,bistrifluoroacetic acid salt

Part A: (S)-tert-Butyl(4-((2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethyl)carbamoyl)cyclohexyl)methylcarbamate

The product from Example 1 Part B (75 mg, 0.15 mmol) andN-(Boc)-tranexamic acid (75 mg, 0.29 mmol) were dissolved in pyridine(1.7 mL). BOP reagent (152 mg, 0.344 mmol) was added and the reactionwas stirred at rt for 12 h. The reaction was diluted with water andextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and evaporated in vacuo. The crudeproduct was carried on to the next step without further purification. MS503.2 (M+H)⁺.

Alternately, the product from Example 1 Part B was coupled with 1.0equivalents of N-Boc-tranexamic acid, 1.2 equivalents HOAt, 5.0equivalents of N-methylmorpholine, and 1.2 equivalents of EDCI. Theamine, N-Boc-tranexamic acid and HOAt are dissolved in DMF.N-Methylmorpholine is added followed by EDCI. The reaction is stirred atrt for 2 and 16 h. The reaction is diluted with EtOAc, washed with ½saturated brine (4-6 times), dried over MgSO₄, filtered and evaporatedto dryness to give the crude product.

Part B:(S)-4-(Aminomethyl)-N-(2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethyl)cyclohexanecarboxamide,bistrifluoroacetic acid salt

The product from Example 2 Part A (100 mg) was dissolved in 30% TFA inCH₂Cl₂ (2.0 mL). The reaction was stirred at rt for 3 h. The reactionwas diluted with toluene and dried in vacuo. The residue wasre-dissolved in toluene and solution evaporated to dryness. The crudeproduct was re-dissolved in MeOH/H₂O (9:1) containing 0.1% TFA and thetitle compound was isolated by prep HPLC (46 mg as the bis-TFA salt, 49%yield). ¹H NMR (500 MHz, d₄-MeOH) δ 1.02-1.11 (m, 2H), 1.32-1.45 (m,2H), 1.54-1.61 (m, 1H), 1.80 (br d, J=12.1 Hz, 1H), 1.86 (br d, J=11.5Hz, 3H), 2.28 (dt, J=12.1, 3.30 Hz, 1H), 2.77 (d, J=7.15 Hz, 2H),3.28-3.33 (dd, 1H, obscured by CH₃OH peak), 3.38 (dd, J=13.5, 8.0 Hz),5.31 (t, J=8.25 Hz, 1H), 7.18 (d, J=7.15 Hz, 2H), 7.22-7.30 (m, 3H),7.43-7.50 (m, 3H), 7.62 (app d, J=6.6 Hz, 2H), 7.75 (s, 1H): MS 403.2(M+H)⁺.

Example 25 (S)-Ethyl2-(4-(2-(1-(4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)phenyl)acetate,bistrifluoroacetic acid salt

Part A: Ethyl 4-acetyl-phenylacetate

Ethyl bromoacetate (1.70 g, 10.2 mmol), tris-(1-naphthylene)phosphine(379 mg, 0.93 mmol) and tribasic potassium phosphate (10.8 g, 51 mmol)were placed in a flask. The flask was evacuated and back-filled withargon. A solution of 4-acetylphenylboronic acid (2.0 g, 12.2 mmol) inanhyd THF (40 mL) was added to the flask. The reaction was stirred at rtfor 16 h. The reaction was diluted with EtOAc, washed with water andbrine, dried over MgSO₄, filtered and evaporated to dryness. The residuewas pre-adsorbed on to SiO₂ and the product isolated via SiO₂chromatography to yield 616 mg (29%) of ethyl 4-acetyl-phenylacetate. MS207.1 (M+H)⁺.

Part B: Ethyl 2-(4-(2-bromoacetyl)phenyl)acetate

Ethyl 4-acetyl-phenylacetate from Example 25 Part A (489 mg, 2.4 mmol)was dissolved in CH₂Cl₂. Bromine (379 mg, 2.4 mmol) was added dropwise.The reaction was stirred at rt for 16 h. The reaction had decolorizedfrom rust red to light yellow. The solvent was evaporated in vacuo toyield 680 mg (99%) of ethyl 2-(4-(2-bromoacetyl)phenyl)acetate as alight yellow oil. The product was used in the next step without furtherpurification. MS 287.0 and 289.0 of equal intensities (M+H)⁺.

Part C: (S)-Ethyl2-(4-(2-(1-(tert-butoxycarbonyl)-2-phenylethyl)-1H-imidazol-4-yl)phenyl)acetate

N-(Boc)-phenylalanine (633 mg, 2.38 mmol) was dissolved in DMF (2.0 mL).Cs₂CO₃ (775 mg, 1.19 mmol) was added to the flask in a single portion,and the reaction was stirred for 1 h. A solution of ethyl2-(4-(2-bromoacetyl)phenyl)acetate from Example 25 Part B (680 mg, 2.38mmol) in DMF (2.0 mL) was added to the reaction vessel, and the reactionwas stirred at rt for 16 h. The solids were filtered off and rinsed withDMF. The organic layers were combined and evaporated to dryness. Theresidue was re-dissolved in EtOAc and washed with a solution of 1:1water and brine, dried over MgSO₄, filtered and evaporated to yield 1.03g of a light tan solid. The solid was re-dissolved in xylenes (14 mL).NH₄OAc (3.42 g, 44 mmol) was added, and the flask fitted with aDean-Stark trap. The reaction was heated to reflux for 5 h with removalof water. The reaction was cooled to rt, and the solvent removed invacuo. The residue was re-dissolved in EtOAc, washed with water andbrine, dried over MgSO₄, filtered and evaporated to yield 951 mg (96%)of a light tan solid. MS 450.1 (M+H)⁺.

Part D: (S)-Ethyl2-(4-(2-(1-amino-2-phenylethyl)-1H-imidazol-4-yl)phenyl)acetate

The product from Example 25 Part C (951 mg, 2.12 mmol) was treatedaccording to the procedure described for Example 1 Part B to yield 1.14g (100%) of a dark brown glass, which was used without furtherpurification in the next step. MS 333.1 (M−NH₂)⁺.

Part E: (S)-Ethyl 2-(4-(2-(1-(4-((tert-butoxycarbonyl)methyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)phenyl)acetate

The product from Example 25 Part D (729 mg, 1.26 mmol),N-(Boc)-tranexamic acid (325 mg, 1.26 mmol) and HOAt (206 mg, 1.51 mmol)were dissolved in DMF (6.3 mL). N-methylmorpholine (637 mg, 6.3 mmol)was added followed by EDCI (289 mmol, 1.51 mmol). The reaction wasstirred at rt for 16 h, diluted with EtOAc, washed with a 1:1 mixture ofwater and brine, dried over MgSO₄, filtered and evaporated to yield 732mg (99%) of product, which was used in the next step without furtherpurification. MS 589.1 (M+H)⁺.

Part F: (S)-Ethyl2-(4-(2-(1-(4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)phenyl)acetate,bistrifluoroacetic acid salt

The product from Example 25 Part E (99 mg, 0.17 mmol) was treated withTFA according to the procedure described for Example 1 Part B. Theproduct was isolated by prep HLPC to yield 61 mg (50%) of the titlecompound as the bis-TFA salt. ¹H NMR (500 MHz, d₄-MeOH) δ 1.02-1.11 (m,2H), 1.24 (t, J=7.15 Hz, 3H), 1.32-1.45 (m, 2H), 1.53-1.61 (m, 1H), 1.80(br d, J=12.6 Hz, 1H), 1.86 (br d, J=11.0 Hz, 3H), 2.28 (tt, J=12.4, 3.0Hz, 1H), 2.775 (d, J=7.15 Hz, 2H), 3.28-3.32 (dd, obscured by MeOHpeak), 3.38 (dd, J=13.5, 8.0 Hz, 1H), 3.70 (s, 2H), 4.145 (q, J=7.15 Hz,2H), 5.31 (t, J=8.5 Hz, 1H), 7.175 (d, J=7.15 Hz, 2H), 7.22-7.30 (m,3H), 7.41 (d, J=8.25, 2H), 7.59 (d, J=8.25 Hz, 2H), 7.74 (s, 1H). HRMS(M+H)⁺ for C₂₉H₃₆N₄O₃, calcd m/z: 489.2866, obs: 489.2861.

Example 26(S)-2-(4-(2-(1-(4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)phenyl)aceticacid, bistrifluoroacetic acid salt

(S)-Ethyl2-(4-(2-(1-(4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)phenyl)acetatebis trifluoroacetic acid salt from Example 25 (30 mg, 0.042 mmol) wasdissolved in MeOH (2 mL) and treated with 1 N NaOH (0.2 mL). Thereaction was stirred at rt for 16 h. The solvent was removed in vacuoand the residue re-dissolved in MeOH/H₂O (9:1) containing 0.1% TFA andthen purified by prep HPLC to yield 22 mg of the title compound as itsbis-TFA salt (76% yield). ¹H NMR (500 MHz, d₄-MeOH) δ 1.02-1.11 (m, 1H),1.31-1.45 (m, 2H), 1.53-1.61 (m, 1H), 1.79 (br d, J=12.1 Hz, 1H), 1.865(br d, J=12.1 Hz, 3H), 2.28 (tt, J=3.2 and 12.1 Hz, 1H), 2.77 (d, J=7.15Hz, 2H), 3.28-3.32 (dd, obscured by MeOH peak), 3.375 (dd, J=8.0 and13.4 Hz, 1H), 3.67 (s, 2H), 5.31 (t, J=8.25 Hz, 1H), 7.175 (d, J=6.6 Hz,2H), 7.22-7.30 (m, 3H), 7.42 (d, J=8.25 Hz, 2H), 7.59 (d, J=8.25 Hz,2H), 7.74 (s, 1H). HRMS (M+H)⁺ for C₂₇H₃₂N₄O₃, calcd m/z: 461.2553, obs:461.2572.

Example 27(S)-4-(Aminomethyl)-N-{1-[(4-carbamoylmethyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-cyclohexanecarboxamide,bistrifluoroacetic acid salt

Part A:(S)-2-(4-(2-(1-(4-((tert-Butoxycarbonyl)methyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)phenyl)aceticacid

The product from Example 25 Part E (200 mg, 0.34 mmol) was dissolved inMeOH (3 mL) and treated with 1 N NaOH (0.34 mL). The reaction wasstirred at rt for 16 h. The solvent was removed in vacuo. The residuewas re-dissolved in MeOH/H₂O (9:1) containing 0.1% TFA. The product wasisolated by prep HPLC (90 mg, 47%). MS 561.1 (M+H)⁺.

Part B: (S)-tert-Butyl(4-((1-(4-(4-(2-amino-2-oxoethyl)phenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)cyclohexyl)methylcarbamate

The product from Example 27 Part A (33 mg, 0.060 mmol) and HOAt (9.7 mg,0.071 mmol) were dissolved in DMF (1 mL). N-Methylmorpholine (18.2 mg,0.18 mmol) and EDCI (13.6 mg, 0.071 mmol) were added sequentially. Thereaction as stirred for 30 min at rt. Conc. aqueous ammonia (5 dropsfrom a Pasteur pipet) was added and the reaction stirred at rt for 16 h.The reaction was diluted with EtOAc and washed with a 1:1 mixture ofwater and brine (5×), 1 N aqueous HCl and brine, dried over MgSO₄,filtered and dried in vacuo. The residue was re-dissolved in MeOH/H₂O(9:1) containing 0.1% TFA, and the product isolated by prep HPLC toyield 9 mg (22%). MS 560.1 (M+H)⁺.

Part C:(S)—N-(1-(4-(4-(2-Amino-2-oxoethyl)phenyl)-1H-imidazol-2-yl)-2-phenylethyl)-4-(aminomethyl)-cyclohexanecarboxamide,bistrifluoroacetic acid salt

The product from Example 27 Part B (9 mg, 0.016 mmol) was treated withTFA according to the procedure described for Example 1 Part B to providethe title compound (11 mg, 99%). ¹H NMR (500 MHz, d₄-MeOH) δ 1.02-1.11(m, 2H), 1.28-1.44 (m, 2H), 1.57 (m, 1H), 1.79 (br d, J=12.6 Hz, 1H),1.85 (br d, J=11 Hz, 3H), 2.28 (tt, J=3.0, 12.1 Hz, 1H), 2.77 (d, J=7.15Hz, 2H), 3.28-3.32 (dd, obscured by MeOH), 3.375 (dd, J=8.0, 13.0 Hz,1H), 3.57 (s, 2H), 5.31 (t, J=8.2 Hz, 1H), 7.175 (d, J=7.2 Hz, 2H),7.22-7.30 (m, 3H), 7.43 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.2 Hz, 2H), 7.74(s, 1H); HRMS (M+H)⁺ for C₂₇H₃₃N₅O₂, calcd m/z: 460.2713, obs: 460.2714.

Example 284-(2-((S)-1-(trans-4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)benzamide,bistrifluoroacetic acid salt

Part A: tert-Butyl(trans-4-(((S)-1-(4-(4-carbamoylphenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)cyclohexyl)methylcarbamate

tert-Butyl(trans-4-(((S)-1-(4-(4-cyanophenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)cyclohexyl)methylcarbamateformed from 2-bromo-4′-cyanoacetophenone using the procedures fromExample 1 Part A-B and Example 2 Part A (117 mg, 0.22 mmol) wasdissolved in DMSO (2 mL) and treated with K₂CO₃ (90.0 mg, 0.65 mmol)under argon. 30% H₂O₂ in water (0.8 mL, 2.4 mmol) and magnesium oxide(44 mg, 1.11 mmol) were added sequentially to the reaction. The reactionwas stirred at rt for 4 h. The reaction was diluted with EtOAc, washedwith 1 N HCl and brine, dried over MgSO₄, filtered and evaporated todryness. The product (109 mg, 90% yield) was isolated as a yellow solid.MS 546.3 (M+H)⁺.

Part B:4-(2-((S)-1-(trans-4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)benzamide,bistrifluoroacetic acid salt

The product from Example 28 Part A (109 mg, 0.20 mmol) was treated withTFA according to the procedure described for Example 2 Part B. Theproduct was isolated by prep HLPC to yield 17.3 mg of the title compound(20%). ¹H NMR (500 MHz, d₄-MeOH) δ 0.36 (m, 2H), 0.68 (m, 2H), 0.87 (m,1H), 1.14 (m, 3H), 2.07 (d, J=7.15 Hz, 2H), 2.63 (m, 2H), 4.61 (t,J=8.25 Hz, 1H), 6.47 (d, J=7.15 Hz, 2H), 6.53 (t, J=7.42 Hz, 1H), 6.58(t, J=7.15 Hz, 2H), 7.04 (d, J=8.25 Hz, 2H), 7.14 (s, 1H), 7.28 (d,J=8.25 Hz, 2H); HRMS (M+H)⁺ for C₂₆H₃₁N₅O₂, calcd m/z: 446.2556, obs:446.2570.

Example 293-(2-((S)-1-(4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)benzamide,bistrifluoroacetic acid salt

The title compound was synthesized by appropriate application of theprocedures described for Example 28. ¹H NMR (500 MHz, d₄-MeOH) δ 1.06(m, 2H), 1.39 (m, 2H), 1.57 (m, 1H), 1.80 (d, J=12.10 Hz, 1H), 1.86 (d,J=11.55 Hz, 3H), 2.28 (tt, J=12.10, 3.30 Hz, 2H), 2.77 (d, J=7.15 Hz,2H), 3.34 (d, J=8.25 Hz, 1H), 3.39 (dd, J=13.40, 8.25 Hz, 1H), 3.98 (s,1H), 5.34 (t, J=8.25 Hz, 1H), 7.19 (d, J=6.60 Hz, 2H), 7.24 (t, J=7.15Hz, 1H), 7.29 (t, J=7.15 Hz, 2H), 7.60 (t, J=7.70 Hz, 1H), 7.82 (m,J=5.50 Hz, 2H), 7.93 (d, J=8.25 Hz, 1H) 8.18 (s, 1H); MS 446.2 (M+H)⁺.

Example 304-(2-((S)-1-(trans-4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)-N-methylbenzamide,bistrifluoroacetic acid salt

Part A:4-(2-((S)-1-(trans-4-((tert-Butoxycarbonyl)methyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)benzoicacid

Methyl4-(2-((S)-1-(trans-4-((tert-butoxycarbonyl)methyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)benzoateformed from 2-bromo-4′-carboxymethylacetophenone using the proceduresfrom Example 1 Part A-B and Example 2 Part A (162 mg, 0.28 mmol) wasdissolved in MeOH (5 ml) and EtOAc (1 mL). 1 N NaOH (2 mL) and magnesiumoxide (112 mg, 2.8 mmol) were added sequentially and the mixture wasstirred for 5 hrs at rt. The solvent was evaporated to dryness in vacuo.The residue was diluted with water and treated with 1 N HCl. Theresulting solution was diluted with EtOAc, washed with brine and driedover MgSO₄, filtered and evaporated to yield 75 mg (60% yield) of aclear glass. MS 548.0 (M+H)⁺.

Part B: tert-Butyl(trans)-4-(((S)-1-(4-(4-(methylcarbamoyl)phenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)cyclohexyl)methylcarbamate

The product from Example 30 Part A (45 mg, 0.08 mmol) and methylamine(0.2 mL, 0.09 mmol) were treated under the conditions described inExample 2 Part B with the substitution of HOBt for HOAt. The resultingyellow oil (44.0. mg, 93% yield) was carried to the next step withoutfurther purification. MS 560.1 (M+H)⁺.

Part C:4-(2-((S)-1-(trans)-4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)-N-methylbenzamide,bistrifluoroacetic acid salt

The product from Example 30 Part B (44.0 mg, 0.079 mmol) was treatedwith TFA according the procedure described for Example 2 Part B. Theresulting residue was re-dissolved in MeOH/H₂O (9:1) containing 0.1% TFAand isolated by prep HPLC to yield 1.0 mg of the title compound (3%). ¹HNMR (500 MHz, d₄-MeOH) δ 1.05 (m, 1H), 1.39 (ddd, J=30.24, 12.92, 3.02Hz, 1H), 1.55 (m, J=12.10 Hz, 1H), 1.79 (m, 1H), 1.86 (d, J=11.00 Hz,1H), 2.26 (m, 1H), 2.77 (d, J=7.15 Hz, 1H), 2.92 (s, 1H), 3.15 (m, 1H),3.3 (m, 2H), 5.29 (t, J=8.25 Hz, 1H), 7.16 (d, J=7.15 Hz, 1H), 7.23 (t,J=7.15 Hz, 1H), 7.28 (t, J=7.15 Hz, 1H), 7.72 (d, J=8.25 Hz, 1H), 7.86(s, 1H), 7.92 (d, J=8.80 Hz, 1H); HRMS (M+H)⁺ for C₂₇H₃₃N₅O₂, calcd m/z:460.2713, obs: 460.2735.

Example 31(S)-4-(2-(1-trans-(4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)-N,N-dimethylbenzamide,bistrifluoroacetic acid salt

The title compound was synthesized by appropriate application of theprocedures described for the synthesis of Example 30. ¹H NMR (500 MHz,d₄-MeOH) δ 1.06 (m, 2H), 1.39 (m, 2H), 1.57 (m, 1H), 1.81 (d, J=14.85Hz, 1H), 1.86 (d, J=10.45 Hz, 3H), 2.28 (tt, J=12.30, 3.30 Hz, 1H), 2.77(d, J=7.15 Hz, 2H), 3.01 (s, 3H), 3.12 (s, 3H), 3.39 (dd, J=13.30, 8.24Hz, 1H), 5.31 (t, J=8.25 Hz, 1H), 7.18 (d, J=7.15 Hz, 2H), 7.24 (t,J=7.15 Hz, 1H), 7.29 (t, J=7.42 Hz, 2H), 7.55 (d, J=8.25 Hz, 2H), 7.72(d, J=8.25 Hz, 2H), 7.85 (s, 1H); HRMS (M+H)⁺ for C₂₈H₃₅N₅O₂, calcd m/z:474.2870, obs: 474.2875.

Example 32trans-N—((S)-1-(4-(1H-Benzo[d]imidazol-2-yl)-1H-imidazol-2-yl)-2-phenylethyl)-4-(aminomethyl)cyclohexanecarboxamide,tristrifluoroacetic acid salt

Part A: (S)-tert-Butyl2-phenyl-1-(4-(trifluoromethyl)-1H-imidazol-2-yl)ethylcarbamate

To a solution of sodium acetate (0.88 g, 6.44 mmol) in 3 mL of water wasadded 1,1-dibromotrifluoroacetone (0.87 g, 3.22 mmol). The mixture washeated at 90° C. under N₂ for 30 min. It was cooled to 0° C. and asolution of (S)-(−)-2-(t-butoxycarbonylamino)-3-phenylpropanal (1.73 g,2.93 mmol) in 15 mL of methanol was added, followed by concentratedammonium hydroxide (4 mL of concentrated solution). The resultingmixture was stirred at RT under N₂ for 12 h. The solvent was removed andwater was added. The precipitate was filtered and then re-dissolved inEtOAc. The EtOAc solution was washed with brine, dried over Na₂SO₄, andfiltered. The filtrate was concentrated to give 0.80 g of the desiredproduct as an off-white solid (76.9% yield). MS, 356.30 (M+H)⁺.

Part B: (S)-tert-Butyl2-phenyl-1-(4-(trimethoxymethyl)-1H-imidazol-2-yl)ethylcarbamate

The product from Example 32 Part A (0.1 g, 0.4 mmol) was dissolved inMeOH (2 mL) and treated with NaOMe (25% wt in MeOH, 1.7 mL, 7.4 mmol).The reaction mixture was heated using microwave irradiation in a sealedtube for 5 min at 100° C. Upon cooling to rt, the solvent was removedunder vacuum, and the residue dissolved in EtOAc (15 mL). The solutionwas washed with H₂O, brine, dried over Na₂SO₄, filtered, and evaporatedto dryness to yield a brown gum (0.15 g). MS 392.1 (M+H)⁺.

Part C: tert-Butyl(trans-4-(((S)-1-(4-(1H-benzo[d]imidazol-2-yl)-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)cyclohexyl)methylcarbamate

The crude intermediate from Example 32 Part B was dissolved in THF (2mL). 1,2-Phenylenediamine (41 mg, 0.38 mmol) and p-toluenesulfonic acidmonohydrate (7.3 mg, 0.038 mmol) were added to the reaction. Thereaction was stirred at rt for 6 h and the solvent removed in vacuo. Theresidue was dissolved in EtOAc and washed with saturated aqueous NaHCO₃and brine, dried over Na₂SO₄, filtered and evaporated to dryness. Theresidue was purified by flash chromatography (silica gel, 0-100% EtOAcin hexane gradient) to yield 59 mg (37%), as a yellow solid. HRMS m/zCalc'd for C₂₃H₂₆N₅O₂ [M+H]⁺: 404.2087. Found 404.2079.

Part D:trans-N—((S)-1-(4-(1H-Benzo[d]imidazol-2-yl)-1H-imidazol-2-yl)-2-phenylethyl)-4-(aminomethyl)cyclohexanecarboxamide,bistrifluoroacetic acid salt

The product from Example 32 Part C (59 mg, 0.15 mmol) was dissolved inCH₂Cl₂ (0.7 mL) and treated with neat TFA (0.3 mL, 30% v/v). Thereaction was stirred at rt for 1 h. The solvent and TFA were removed invacuo. The residue was redissolved in DMF (1 mL). Et₃N (0.073 mL, 0.53mmol), N-Boc-tranexamic acid (42 mg, 0.16 mmol), HOBt (0.03 g, 0.23mmol), and EDCI (43 mg, 0.23 mmol) were added and the reaction wasstirred at rt for 4 h. EtOAc (15 mL) was added, followed by H₂O (10 mL).The separated organic phase was washed with water, brine, dried overNa₂SO₄, filtered and evaporated to dryness. The residue was dissolved inCH₂Cl₂ (0.7 mL) and treated with neat TFA (0.3 mL, 30% v/v). After 40min. at rt, the reaction was concentrated. Purification by Prep HPLCgave 66 mg (56%) of the title compound. ¹H NMR (400 MHz, CD₃OD) δ0.99-1.09 (m, 2H), 1.27-1.49 (m, 2H), 1.54-1.60 (m, 1H), 1.69-1.72 (m,1H), 1.82-1.85 (m, 3H), 2.16-2.23 (m, 1H), 2.76 (d, J=7.0 Hz, 2H), 3.20(dd, J=8.8, 13.6 Hz, 1H), 3.46 (dd, J=6.6, 13.6 Hz, 1H), 5.35 (dd,J=7.0, 8.8 Hz, 1H), 7.16-7.26 (m, 5H), 7.54-7.58 (m, 2H), 7.72-7.76 (m,2H), 8.04 (s, 1H); HRMS m/z Calc'd for C₂₆H₃₁N₆O [M+H]⁺: 443.2559. Found443.2545.

Examples 33 to 35 listed in Table 2 were similarly synthesized byappropriate application of the procedures described for Example 32.

Example 36 Methyl2-(2-((S)-1-(trans-4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)thiazole-4-carboxylate,bistrifluoroacetic acid salt

Part A: Methyl2-(2-((S)-1-(tert-butoxycarbonyl)-2-phenylethyl)-1H-imidazol-4-yl)-4,5-dihydrothiazole-4-carboxylate

(S)-tert-Butyl2-phenyl-1-(4-(trifluoromethyl)-1H-imidazol-2-yl)ethylcarbamate producedin Example 32 Part A (0.43 g, 1.21 mmol) was dissolved in MeOH (5 mL).NaOMe (25% wt in MeOH, 5.5 mL, 24.2 mmol) was added. The reactionmixture was heated for 42 h at 60° C., then cooled to rt. The solventwas removed under vacuum, and the residue dissolved in EtOAc (50 mL).The solution was washed with H₂O, brine, dried over Na₂SO₄, filtered andevaporated to dryness to yield a brown gum (0.54 g). A portion of thecrude intermediate (0.19 g) was dissolved in THF (5 mL). L-cysteinemethyl ester hydrochloride (0.073 g, 0.43 mmol) and CSA (0.01 g, 0.043mmol) were added to the reaction. The reaction was stirred at rt for 22h and the solvent was removed in vacuo. The residue was purified byflash chromatography to yield 0.022 g of the desired product (12%) as ayellow solid. MS 431.08 (M+1)⁺.

Part B: Methyl2-(2-((S)-1-(tert-butoxycarbonyl)-2-phenylethyl)-1H-imidazol-4-yl)thiazole-4-carboxylate

The product from Example 36 Part A (0.022 g, 0.051 mmol) was dissolvedin toluene (1 mL) and treated with MnO₂ (0.067 g, 0.77 mmol). Thereaction was stirred at rt for 5 h. The reaction mixture was filtered,and the filter cake washed with EtOAc. The combined filtrates wereconcentrated to dryness. The residue was purified by flashchromatography to yield 0.017 g of the triazole (78%) as a white solid.HRMS m/z Calc'd for C₂₁H₂₅N₄O₅S [M+H]⁺: 429.1597. Found 429.1586.

Part C: Methyl2-(2-((S)-1-(trans-4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)thiazole-4-carboxylate,bistrifluoroacetic acid salt

The product from Example 36 Part B was deprotected with TFA, coupledwith N-(Boc)-tranexamic acid, and then deprotected following by the sameprocedures described in Example 32 Part D to give the title compound,after purification by Prep HPLC (0.014 g, 50%). ¹H NMR (400 MHz, CD₃OD)δ 0.96-1.10 (m, 2H), 1.27-1.47 (m, 2H), 1.51-1.61 (m, 1H), 1.72-1.89 (m,4H), 2.18-2.28 (m, 1H), 2.76 (d, J=7.0 Hz, 2H), 3.25-3.35 (m, 2H), 3.94(s, 3H), 5.31 (t, J=7.9 Hz, 1H), 7.17-7.28 (m, 5H), 7.98 (s, 1H), 8.43(s, 1H); HRMS m/z Calc'd for C₂₄H₃₀Cl₂N₅O₃S (M+H)⁺: 468.2069. Found468.2063.

Example 37 Methyl2-((S)-1-(trans-4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazole-4-carboxylate,bistrifluoroacetic acid salt

Part A: (S)-Methyl 2-(1-amino-2-phenylethyl)-1H-imidazole-4-carboxylate

The product formed in Example 32 Part B (492 mg, 1.43 mmol) was treatedaccording to the procedure described for Example 1 Part B to yield 350mg of the product (99%). MS 244.22 (M−1)⁻.

Part B: Methyl2-((S)-1-trans)-4-((tert-butoxycarbonyl)methyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazole-4-carboxylate

The product formed in Example 37 Part A (350 mg, 1.4 mmol) was coupledwith N-(Boc)-tranexamic acid according to the procedure described forExample 2 Part A to yield 290 mg of the product (43%). MS 485.22 (M+H)⁺.

Part C: Methyl2-((S)-1-(trans-4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazole-4-carboxylate,bistrifluoroacetic acid salt

The product formed in Example 37 Part B (290 mg, 0.60 mmol) was treatedaccording to the procedure described for Example 2 Part B to yield thetitle compound (138 mg, 49%). ¹H NMR (500 MHz, d₄-MeOH) δ 1.05 (ddd,J=12.51, 8.66, 4.12 Hz, 3H) 1.36 (ddd, J=29.14, 12.65, 3.30 Hz, 3H) 1.56(dd, J=7.15, 3.85 Hz, 1H) 1.75 (d, J=12.10 Hz, 1H) 1.84 (dd, J=10.17,2.47 Hz, 4H) 2.21 (m, 1H) 2.63 (d, J=9.35 Hz, 1H) 2.76 (d, J=7.15 Hz,3H) 3.24 (dd, J=7.97, 2.47 Hz, 3H) 3.88 (s, 4H) 5.24 (t, J=7.97 Hz, 1H)7.12 (d, J=7.15 Hz, 3H) 7.20 (t, J=7.15 Hz, 1H) 7.25 (m, 3H) 7.86 (s,1H); MS 385.33 (M+H)⁺.

Example 382-((S)-1-(trans-4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazole-4-carboxylicacid, bistrifluoroacetic acid salt

Part A:2-((S)-1-(trans)-4-((tert-Butoxycarbonyl)methyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazole-4-carboxylicacid

The product from Example 37 Part B (290 mg, 0.62 mmol) was dissolved ina solution of MeOH (2 mL) and 1 N NaOH (4 mL) and stirred for 72 hrs atrt. The solvent was evaporated to dryness. The residue was diluted withwater and treated with 1 N HCl. The resulting solution was diluted withEtOAc, washed with brine, dried over MgSO₄, filtered and evaporated toyield 138 mg of the acid (49%). MS 471.05 (M+1)⁺.

Part B:2-((S)-1-(trans-4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazole-4-carboxylicacid, bistrifluoroacetic acid salt

The product from Example 38 Part A (50 mg, 0.11 mmol) was treated withthe TFA according the procedure described for Example 2 Part B. Theresulting residue was re-dissolved in MeOH/H₂O (9:1) containing 0.1% TFAand isolated by prep HPLC to yield 17.1 mg of the title compound (44%).¹H NMR (500 MHz, d₄-MeOH) δ 0.93 (m, 3H), 1.24 (m, 3H), 2.12 (m, 1H),2.64 (d, J=6.87 Hz, 3H), 2.73 (s, 1H), 2.86 (s, 1H), 3.13 (dd, J=13.75,8.25 Hz, 1H), 3.2 (m, 2H), 7.01 (d, J=6.87 Hz, 3H), 7.11 (d, J=7.33 Hz,1H), 7.15 (t, J=7.33 Hz, 3H), 7.81 (s, 1H); HRMS (M+H)⁺ for C₂₀H₂₆N₄O₃,calcd m/z: 371.2083, obs: 371.2072.

Example 39 Ethyl2-(2-((S)-1-(trans-4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazole-4-carboxamido)acetate,bistrifluoroacetic acid salt

Part A: Ethyl2-(2-((S)-1-(trans-4-((tert-butoxycarbonyl)methyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazole-4-carboxamido)acetate

The product from Example 38 Part A (30.0 mg, 0.06 mmol) and ethyl2-aminoacetate (10 mg, 0.09 mmol) were treated under the conditionsdescribed in Example 2 Part A with the substitution of HOBt (10 mg, 0.09mmol) for the HOAt. The resulting yellow oil (33.0. mg, 97% yield) wascarried to the next step without further purification. MS 556.45 (M+H)⁺.

Part B: Ethyl2-(2-((S)-1-(trans-4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazole-4-carboxamido)acetate,bistrifluoroacetic acid salt

The product from Example 39 Part A (33.0 mg, 0.06 mmol) was treated withTFA according the procedure described for Example 1 Part B. Theresulting residue was re-dissolved in MeOH/H₂O (9:1) containing 0.1% TFAand isolated by prep HPLC to yield 2.0 mg of the title compound (7%). ¹HNMR (500 MHz, d₄-MeOH) δ 1.03 (m, 3H), 1.27 (t, J=7.15 Hz, 4H), 1.37 (m,3H), 1.56 (m, 2H), 1.72 (d, J=13.20 Hz, 1H), 1.83 (dd, J=8.80, 3.85 Hz,4H), 2.20 (m, 1H), 2.76 (d, J=7.15 Hz, 3H), 3.19 (dd, J=13.75, 8.25 Hz,1H), 3.25 (m, 2H), 4.10 (s, 3H), 4.20 (q, J=7.15 Hz, 3H), 5.25 (t,J=7.70 Hz, 1H), 7.16 (t, J=7.15 Hz, 3H), 7.19 (d, J=7.15 Hz, 1H), 7.24(t, J=7.15 Hz, 3H), 7.67 (s, 1H): HRMS (M+Na)⁺ for C₂₄H₃₃N₅O₄, calcdm/z: 478.2403, obs: 478.2453.

Example 42 Methyl2-((S)-1-(trans-4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate,bistrifluoroacetic acid salt

Part A: (S)-Methyl2-(1-(tert-butoxycarbonyl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate

To a solution of L-N-(Boc)-phenylalanine (265 mg, 1.0 mmole) and BOPreagent (464 mg, 1.0 mmole) in pyridine (10 mL) was added methyl3,4-diaminobenzoate (166 mg, 1.0 mmole). The reaction mixture wasstirred at 80° C. for 3 d. The solvent was removed under vacuum. Theresidue was re-dissolved in EtOAc. The solution was washed with waterand brine, dried over Na₂SO₄, filtered and evaporated to dryness. Thecrude product was purified by prep HPLC to yield 178 mg of the amide(45%). MS 340.2 (M+H)⁺.

Part B: (S)-Methyl2-(1-amino-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate

The product formed in Example 42 Part A (178 mg, 0.45 mmol) was treatedwith TFA according to the procedure described for Example 1 Part B toyield 180 mg of the amine (76%). MS 296.2 (M+H)⁺.

Part C: Methyl2-((S)-1-(trans-4-((tert-butoxycarbonyl)methyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate

The product formed in Example 42 Part B (178 mg, 0.34 mmol) was coupledwith N-(Boc)-tranexamic acid according to the procedure described forExample 2 Part A to yield 75 mg of the desired product (41%). MS 535.5(M+H)⁺.

Part D: Methyl2-((S)-1-(trans-4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate,bistrifluoroacetic acid salt

The product formed in Example 42 Part C (15 mg, 0.028 mmol) was treatedwith TFA according to the procedure described for Example 2 Part B toyield 12 mg of the title compound (65%). ¹H NMR (500 MHz, d₄-MeOH) δ1.04-1.10 (m, 2H), 1.29-1.42 (m, 2H). 1.52-1.60 (m, 1H), 1.75 (m, 1H),1.83-1.86 (m, 3H), 2.27-2.29 (m, 1H), 2.77, (d, J=7.15 Hz, 2H), 3.45 (m,2H), 3.96 (s, 3H), 5.48 (t, J=8.25 Hz, 1H), 7.22-7.26 (m, 5H), 7.80 (d,J=7.0 Hz, 1H), 8.19 (dd, J=7.0 Hz, 1.2 Hz, 1H), 8.36 (s, 1H); MS 435.3(M+H)⁺.

Example 432-((S)-1-(trans-4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylicacid, bistrifluoroacetic acid salt

Part A:2-((S)-1-(trans-4-((tert-Butoxycarbonyl)methyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylicacid

The compound from Example 42 Part C (50 mg, 0.093 mmol) was hydrolyzedusing conditions described for Example 38 Part A with the exception thatethanol was used in place of methanol yielding 38 mg of the acid (78%).MS 521.3 (M+H)⁺.

Part B:2-((S)-1-(trans-4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylicacid, bistrifluoroacetic acid salt

The compound from Example 43 Part A (15 mg, 0.029 mmol) was converted tothe title product using the procedure described for Example 2 Part B (12mg, 64%). ¹H NMR (400 MHz, d₄-MeOH) δ 1.04-1.10 (m, 2H), 1.29-1.42 (m,2H), 1.56 (m, 1H), 1.75 (m, 1H), 1.83-1.86 (m, 3H), 2.27-2.28 (m, 1H),2.77 (d, J=7.03 Hz, 2H), 3.43 (d, J=8.34 Hz, 2H), 5.48 (t, J=8.12 Hz,1H), 7.22-7.26 (m, 5H), 7.80 (d, J=8.78 Hz, 1H), 8.19 (dd, J=8.35 Hz and1.3 Hz, 1H), 8.36 (s, 1H); MS 421.2 (M+H)⁺.

Example 442-((S)-1-(trans-4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxamide,bistrifluoroacetic acid salt

Part A: tert-Butyl(trans-4-(((S)-1-(5-carbamoyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)carbamoyl)cyclohexyl)methylcarbamate

The compound from Example 43 Part A (23 mg, 0.044 mmol) was subjected tothe conditions described for Example 1 Part C with the exception thatammonium hydroxide was used in place of 4-amidinobenzoic acidhydrochloride to provide 18 mg of the desired product (79%). MS 520.0(M+H)⁺.

Part B:2-((S)-1-(trans-4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxamide,bistrifluoroacetic acid salt

The compound from Example 44 Part A (18 mg, 0.034 mmol) was reacted withTFA following the conditions described for Example 2 Part B to yield 8mg of the title compound (36%). ¹H NMR (500 MHz, d₄-MeOH) δ 1.04-1.10(m, 2H), 1.29-1.42 (m, 2H), 1.56 (m, 1H), 1.75 (m, 1H), 1.83-1.86 (m,3H), 2.27-2.28 (m, 1H), 2.77 (d, J=7.14 Hz, 2H), 3.43 (d, J=7.70 Hz,2H), 5.48 (t, J=8.24 Hz, 1H), 7.22-7.27 (m, 5H), 7.80 (d, J=8.78 Hz,1H), 8.05 (dd, J=8.79 Hz, 1.64 Hz, 1H), 8.25 (s, 1H); MS 420.2 (M+H)⁺.

Example 45 Ethyl2-(2-((S)-1-(trans-4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-benzo[d]imidazol-5-yl)acetate,bistrifluoroacetic acid salt

Part A: Ethyl 2-(4-amino-3-nitrophenyl)acetate

To a solution of 4-(aminophenyl)acetic acid ethyl ester (538 mg, 3.0mmole) in acetic acid (20 mL) was added nitric acid (90%, 420 mg, 6mmole). The reaction mixture was stirred at 100° C. for 4 h. Thereaction was cooled to rt. Acetic acid was partially removed undervacuum. The residue was diluted with EtOAc. The pH of the solution wasadjusted to 8-9 with 10% NaOH. It was washed with water and brine, driedover Na₂SO₄, filtered and evaporated. The crude product was isolated bysilica gel chromatography to give 128 mg (20% yield) of a bright yellowsolid. It was taken into the next step without further purification.

Part B: Ethyl 2-(3,4-diaminophenyl)acetate

To a suspension of 10% palladium on carbon (15 mg) in 2 mL of MeOH wasadded a solution of the product from Example 45 Part A (128 mg) in MeOH(8 mL). The reaction mixture was stirred under one atmosphere ofhydrogen at rt for 4 h. The catalyst was filtered. To the filtrate wasadded 1 N HCl (0.1 mL) and the solvent was evaporated to dryness toyield 130 mg the crude product as the HCl salt (86% yield). MS 195.2(M+H)⁺.

Part C: (S)-Ethyl2-(2-(1-(tert-butoxycarbonyl)-2-phenylethyl)-1H-benzo[d]imidazol-5-yl)acetate

The product from Example 45 Part B (130 mg, 0.49 mmol) andL-N-(Boc)-phenylalanine (130 mg, 0.49 mmol) were subjected to theconditions described for Example 42 Part A to yield 210 mg (100% yield)of the desired product. MS 424.3 (M+H)⁺.

Part D: Ethyl2-(2-((S)-1-(trans-4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-benzo[d]imidazol-5-yl)acetate,bistrifluoroacetic acid salt

The product from Example 45 Part C was treated with TFA and then coupledwith N-(Boc)-tranexamic acid according to the procedures described forExample 2 Part A to yield the desired product which was reacted with TFAfollowing the conditions described for Example 2 Part B to yield thetitle compound. MS 463.43 (M+H)⁺. ¹H NMR (500 MHz, d₄-MeOH) δ 1.05 (m,2H), 1.24 (t, J=3.30 Hz, 3H), 1.35 (m, 2H), 1.56 (m, 1H), 1.78 (br d,J=12.65 Hz, 1H), 1.86 (m, 3H), 2.28 (m, 1H), 2.77 (d, J=7.15 Hz, 2H),3.31 (s, 2H), 3.42 (d, J=7.70 Hz, 2H), 3.84 (s, 2H), 4.16 (q, J=7.15 Hz,2H), 5.46 (t, J=8.25 Hz, 1H), 7.23 (m, 5H), 7.51 (d, J=8.80 Hz, 1H),7.68 (d, J=8.80 Hz, 2H); MS 463.4 (M+H)⁺.

Example 462-(2-((S)-1-(trans-4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-benzo[d]imidazol-5-yl)aceticacid, bistrifluoroacetic acid salt

The product from Example 45 Part D was hydrolyzed with LiOH and thentreated with TFA following the conditions described for Example 2 Part Bto yield the title compound. MS 435.4 (M+H)⁺. ¹H NMR (500 MHz, d₄-MeOH)δ 1.05 (m, 2H), 1.35 (m, 2H), 1.55 (m, 1H), 1.78 (br d, J=12.10 Hz, 1H),1.86 (m, 3H), 2.28 (m, 1H), 2.77 (d, J=6.60 Hz, 2H), 3.31 (s, 2H), 3.42(d, J=8.25 Hz, 2H), 3.82 (s, 2H), 5.46 (t, J=8.25 Hz, 1H), 7.23 (m, 5H),7.52 (d, J=8.24 Hz, 1H), 7.67 (d, J=8.25 Hz, 2H); MS 435.4 (M+H)⁺.

Example 47trans-N—((S)-1-(5-(2-Amino-2-oxoethyl)-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(aminomethyl)cyclohexanecarboxamide,bistrifluoroacetic acid salt

This compound was prepared from the product from Example 45 Part D usingthe same procedures described for the synthesis of Example 44. ¹H NMR(500 MHz, d₄-MeOH) δ 1.06 (m, 2H), 1.35 (m, 2H), 1.55 (m, 1H), 1.78 (brd, J=11.86 Hz, 1H), 1.86 (m, 3H), 2.28 (m, 1H), 2.77 (d, J=7.03 Hz, 2H),3.31 (s, 2H), 3.42 (d, J=8.35 Hz, 2H), 3.70 (s, 2H), 5.46 (t, J=8.35 Hz,1H), 7.23 (m, 5H), 7.52 (d, J=8.35 Hz, 1H), 7.67 (d, J=8.325 Hz, 2H); MS434.3 (M+H)⁺.

Example 48trans-4-(Aminomethyl)-N—((S)-2-phenyl-1-(5-phenyloxazol-2-yl)ethyl)cyclohexanecarboxamide,bistrifluoroacetic acid salt

Part A:(S)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-(2-oxo-2-phenyl-ethyl)-3-phenyl-propionamide

N-Phthaloyl-L-phenylalanine (290 mg, 1 mmol) and 2-aminoacetophenone(171 mg, 1 mmol) were dissolved in 10 mL of pyridine. Bop reagent (470mg, 1.1 mmol) was added The mixture was stirred at rt under N₂ for 12 h.The solvent was removed. The residue was dissolved in EtOAc and washedwith water and sat. NaHCO₃. The organic layer was dried over Na₂SO₄,filtered, and concentrated to yield 412 mg of the product (100% yield).MS 413.2 (M+H)⁺.

Part B:(S)-2-(2-Phenyl-1-(5-phenyloxazol-2-yl)ethyl)isoindoline-1,3-dione

The product from Example 48 Part A (412 mg, 1 mmol) was dissolved in DMFand treated with phosphorous oxychloride (460 mg, 3 mmol) at 90° C.according to the procedure described by Dow, R. et al. (J. Org. Chem.,55:386 (1990)) to yield 160 mg (41% yield) of the product. MS 395.2(M+H)⁺.

Part C: (S)-2-Phenyl-1-(5-phenyloxazol-2-yl)ethanamine

A solution of the product from Example 48 Part B (160 mg, 0.4 mmol) inEtOH (10 mL) was added to hydrazine (39 mg, 1.2 mmol). The reactionmixture was refluxed for 2 h. It was cooled to rt. EtOH was removedunder vacuum. The residue was re-dissolved in dichloromethane. Theundissolved solid was removed by filtration. The filtrate wasconcentrated to yield 95 mg of the product as a yellow solid (90%yield). MS 265.1 (M+H)⁺.

Part D:trans-4-(Aminomethyl)-N—((S)-2-phenyl-1-(5-phenyloxazol-2-yl)ethyl)cyclohexanecarboxamide,bistrifluoroacetic acid salt

The product from Example 48 Part C (95 mg, 0.35 mmol) was converted tothe title compound by sequential application of the procedures describedfor Example 2 Part A and Part B (26%). ¹H NMR (500 MHz, d₄-MeOH) δ1.04-1.10 (m, 2H), 1.29-1.42 (m, 2H), 1.56 (m, 1H), 1.75 (m, 1H),1.83-1.86 (m, 3H), 2.22 (m, 1H), 2.77 (d, J=7.14 Hz, 2H), 3.20 (m, 1H),3.33 (m, 1H), 5.41 (m, 1H), 7.22-7.27 (m, 5H), 7.34 (t, J=7.15 Hz, 1H),7.42 (m, 3H), 7.63-7.65 (d, J=8.25 Hz, 2H); MS 404.3 (M+H)⁺.

Example 49trans-4-(Aminomethyl)-N—((S)-2-phenyl-1-(5-phenyl-2H-1,2,4-triazol-3-yl)ethyl)cyclohexane-carboxamide,bistrifluoroacetic acid salt

Part A: (S)-tert-Butyl2-phenyl-1-(5-phenyl-2H-1,2,4-triazol-3-yl)ethylcarbamate

L-N-(Boc)-phenylalanine (265 mg, 1 mmole) and hydrazine (64 mg, 2 mmol)were combined using the conditions described for Example 1 Part C toform 279 mg of hydrazoic acid (100% yield). MS 280.1 (M+H)⁺. To asolution of hydrazoic acid (279 mg, 1.0 mmole) and Et₃N (161 mg, 1.6mmole) in 10 mL of acetonitrile was added ethylbenzimidate hydrochloride(278 mg, 1.5 mmole). The reaction was heated to reflux for 24 h. Thereaction was cooled to rt and diluted with EtOAc. The mixture was washedwith water and brine, dried over Na₂SO₄, filtered and evaporated todryness in vacuo. The crude product was purified by prep HPLC to yield154 mg of an oil (42% yield). MS 365.2 (M+H)⁺.

Part B:trans-4-(Aminomethyl)-N—((S)-2-phenyl-1-(5-phenyl-2H-1,2,4-triazol-3-yl)ethyl)cyclohexane-carboxamide,bistrifluoroacetic acid salt

The product from Example 49 Part A (154 mg, 0.42 mmol) was converted tothe title compound by sequential application of the procedures describedfor Example 1 Part B, Example 2 Part A and Part B (28%). ¹H NMR (400MHz, d₄-MeOH) δ 1.02-1.06 (m, 2H), 1.29-1.42 (m, 2H), 1.56 (m, 1H), 1.75(m, 1H), 1.83-1.86 (m, 3H), 2.21 (m, 1H), 2.77 (d, J=7.03 Hz, 2H),3.18-3.21 (m, 1H), 3.31 (m, 1H), 5.42 (t, J=8.12 Hz, 1H), 7.22-7.26 (m,5H), 7.51-7.52 (m, 3H), 7.96-7.98 (m, 2H); MS 404.2 (M+H)⁺.

Example 50trans-4-(Aminomethyl)-N—((S)-2-phenyl-1-(3-phenyl-1H-pyrazol-5-yl)ethyl)cyclohexanecarboxamide,bistrifluoroacetic acid salt

Part A: 3-Oxo-3-phenylpropanoic acid

To a solution of ethyl benzoyl acetate (2.88 g, 15 mmol) in EtOH (30 mL)was added 1N NaOH (30 mL). The reaction mixture was stirred at rt for 72h. It was cooled to 0° C. and acidified with 1N HCl. EtOH was removedunder reduced pressure. The aqueous layer was extracted twice withdichloromethane. The combined dichloromethane solution was washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo to give alight yellow solid. (600 mg, 24%). MS 165.1 (M+H)⁺.

Part B: (S)-Benzyl 3,5-dioxo-1,5-diphenylpentan-2-yl carbamate

To a solution of the product from Example 50 Part A (600 mg, 3.65 mmol)in THF (20 mL) and MeOH (20 mL) was added magnesium ethoxide (417 mg,3.65 mmol). The mixture was stirred at r.t. for 4 h. The solvents wereremoved under reduced pressure. The crude product was dissolved in DMF(2 mL) and added to a mixture of N-CBZ-L-phenylalanine (800 mg, 2.68mmol), 1,1′-carbonyldiimidazole (520 mg, 3.21 mmol) in DMF (4 mL) whichhad been stirred for 2 h at rt. The resulting mixture was stirred at rtovernight. It was diluted with EtOAc, washed with diluted HCl, water andbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by prep HPLC to give the product (140 mg, 13%). MS402.1 (M+H)⁺.

Part C: ((S)-Benzyl 2-phenyl-1-(3-phenyl-1H-pyrazol-5-yl)ethylcarbamate

To a solution of Example 50 Part B (32 mg, 0.08 mmol) in EtOH (3 mL) wasadded hydrazine hydrate (3 mg, 0.09 mmol). The reaction mixture washeated at 60° C. for 3 h. EtOH was removed in vacuo to give the desiredproduct (0.32 mg, 100%). MS 398.1 (M+H)⁺.

Part D: (S)-2-Phenyl-1-(3-phenyl-1H-pyrazol-5-yl)ethanamine

To a solution from Example 50 Part C in MeOH (3 mL) was added 10% Pd/C(5 mg). The reaction mixture was stirred under H₂ at rt for 4 h. Thecatalyst was removed by filtration. The crude mixture was purified byprep HPLC to give the desired product (12 mg, 57%). MS 262.2 (M−H)⁻.

Part E:trans-4-(Aminomethyl)-N—((S)-2-phenyl-1-(3-phenyl-1H-pyrazol-5-yl)ethyl)cyclohexanecarboxamide,bistrifluoroacetic acid salt

The product from Example 50 Part D (12 mg, 0.046 mmol) was converted tothe title compound by sequential application of the procedures describedfor Example 2 Part A and Part B (11 mg, 46%). ¹H NMR (500 MHz, d₄-MeOH)δ1.02-1.06 (m, 2H), 1.30-1.33 (m, 1H), 1.43-1.46 (m, 1H), 1.56 (m, 1H),1.64 (m, 1H), 1.83 (m, 3H), 2.16-2.18 (m, 1H), 2.75 (d, J=7.03 Hz, 2H),3.08-3.10 (m, 1H), 3.27 (m, 1H), 5.35 (t, J=8.12 Hz, 1H), 6.61 (s, 1H),7.22 (m, 1H), 7.23 (m, 4H), 7.35-7.36 (t, J=7.15 Hz, 1H), 7.41-7.44 (t,J=7.70 Hz, 2H), 7.69-7.71 (d, J=7.15 Hz, 2H); MS 403.1 (M+H)⁺.

Example 51trans-4-(Aminomethyl)-N—((S)-1-(5-oxo-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenylethyl)-cyclohexanecarboxamide,bistrifluoroacetic acid salt Part A: (S)-Benzyl1-(5-oxo-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenylethylcarbamate

A solution of (S)—N—CBZ-phenylalanine nitrile (140 mg, 0.5 mmol) andsodium methoxide (13 mg, 0.24 mmol) in MeOH (4 mL) was stirred at 30° C.for 3 h. Acetic acid (1 mg, 0.2 mmol) was added, followed by phenylhydrazine (108 mg, 1 mmol). The reaction mixture was stirred at rt for18 h. The mixture was cooled to 0° C., and the solid was removed byfiltration. The MeOH solution was purified by silica gel chromatographyto give a yellow oil, which was dissolved in THF (6 mL) and1,1′-carbonyldiimidazole (68 mg, 0.42 mmole) was added. The mixture washeated to reflux for 48 h. The reaction was cooled to rt, diluted withCH₂Cl₂, washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo to give 38 mg (66%) of the product as a red solid.MS 413.2 (M−H)⁻.

Part B:trans-4-(Aminomethyl)-N—((S)-1-(5-oxo-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenylethyl)-cyclohexanecarboxamide,bistrifluoroacetic acid salt

The product of Example 51 Part A (38 mg, 0.09 mmol) was converted to thetitle compound by sequential application of the procedures described forExample 50 Part D, and Example 2 Part A and Part B (8 mg, 17%). ¹H NMR(500 MHz, d₄-MeOH) δ 1.02-1.06 (m, 2H), 1.30-1.33 (m, 1H), 1.43-1.46 (m,1H), 1.56 (m, 1H), 1.67 (m, 1H), 1.81-1.86 (m, 3H), 2.16-2.18 (m, 1H),2.75 (d, J=7.15 Hz, 2H), 3.08-3.10 (m, 1H), 3.31 (m, 1H), 5.15-5.17 (m,1H), 7.19-7.21 (m, 2H), 7.27-7.28 (m, 4H), 7.40-7.43 (t, J=7.97 Hz, 2H),7.85-7.87 (d, J=7.69 Hz, 2H); MS 420.1 (M+H)⁺.

Example 52trans-4-(Aminomethyl)-N—((S)-2-phenyl-1-(2-phenyl-1H-imidazol-4-yl)ethyl)cyclohexane-carboxamide,bistrifluoroacetic acid salt Part A: (S)-Benzyl2-phenyl-1-(2-phenyl-1H-imidazol-4-yl)ethylcarbamate

A solution of (S)-benzyl-4-bromo-3-oxo-1-phenylbutan-2-yl carbamate (376mg, 1.0 mmole) and sodium formate (68 mg, 1.0 mmole) in EtOH (15 mL) washeated to reflux for 14 h. Benzamidine (240 mg, 1.5 mmole) and sodiumbicarbonate (400 mg, 4.7 mmole) were added to the reaction. The reactionmixture was heated to refluxed for an additional 24 h. The reaction wascooled to rt and the dried in vacuo. The residue was re-dissolved inEtOAc, washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by silica gelchromatography to yield 33 mg (8% yield). MS 398.1 (M+H)⁺.

Part B:trans-4-(Aminomethyl)-N—((S)-2-phenyl-1-(2-phenyl-1H-imidazol-4-yl)ethyl)cyclohexane-carboxamide,bistrifluoroacetic acid salt

The product from Example 52 Part A (33 mg, 0.083 mmol) was converted tothe title compound by sequential application of the procedures describedfor Example 50 Part D, and Example 2 Part A and Part B (5 mg, 12%yield). ¹H NMR (400 MHz, d₄-MeOH) δ 1.02-1.06 (m, 2H), 1.30-1.33 (m,1H), 1.43-1.46 (m, 1H), 1.56 (m, 1H), 1.67 (m, 1H), 1.83 (m, 3H),2.16-2.18 (m, 1H), 2.75 (d, J=7.03 Hz, 2H), 3.08-3.10 (m, 1H), 3.31 (m,1H), 5.34-5.36 (m, 1H), 7.22-7.29 (m, 5H), 7.51 (s, 1H), 7.62-7.68 (m,3H), 7.87-7.89 (m, 2H); MS 403.3 (M+H)⁺.

Example 53N-(4-Carbamimidoylphenyl)-3-phenyl-2-(4-phenyl-1H-imidazol-2-yl)propanamide,Bis-trifluoroacetic acid salt

Part A: 2-Benzyl-3-methoxy-3-oxopropanoic acid

Benzyl malonic acid (19.4 g, 0.10 mol) was dissolved in 180 mL of MeOH.The mixture was cooled in an ice-bath and to it was added thionylchloride dropwise over 30 min (7.3 mL, 0.10 mol). The mixture wasstirred in the ice-bath for 30 min and then at RT for 30 min under N₂.The solvent was removed, and the residue was dissolved in aqueousNaHCO₃. The basic solution was extracted with EtOAc to remove thebis-ester which was discarded. The aqueous solution was then acidifiedwith aqueous HCl to pH 5 and extracted with EtOAc. The EtOAc extract waswashed with brine, dried over Na₂SO₄, and concentrated to give 7.2 g of2-benzyl-3-methoxy-3-oxopropanoic acid (35%). MS 209.24 (M+H)⁺.

Part B: Methyl 3-phenyl-2-(4-phenyl-1H-imidazol-2-yl)propanoate

The product from Example 53 Part A (1.04 g, 5.0 mmol) was dissolved inEtOH (13 mL) and a solution of Cs₂CO₃ (0.81 g, 2.5 mmol) in H₂O (13 mL)was added. The reaction mixture was stirred at RT for 1 h under N₂. Thesolvent was removed under vacuum, and the resulting salt was suspendedin DMF (20 mL). 2-Bromoacetophenone (1.3 g, 6.6 mmol) was added in asingle portion, and the reaction stirred at RT under N₂ for 2 h. Thereaction was filtered to remove CsBr. The solids were washed with DMF.The combined washings and filtrate were concentrated in vacuo to yield ayellow solid. The crude intermediate was placed in a flask fitted with aDean-Stark trap and dissolved in xylene (40 mL). NH₄OAc (7.78 g, 100mmol) was added to the flask and the reaction was heated to reflux for 3h. The reaction was cooled to RT and the solvent removed in vacuo. Theresidue was redissolved in EtOAc and washed with saturated aqueousNaHCO₃ and brine, dried over Na₂SO₄, filtered, concentrated, andpurified by flash chromatography (silica gel, EtOAc/hexane) to yield 600mg of the desired product (39%). MS 307.29 (M+H)⁺.

Part C: 3-Phenyl-2-(4-phenyl-1H-imidazol-2-yl)propanoic acid

The product from Example 53 Part B (350 mg, 1.14 mmol) was dissolved in9 mL of EtOH and 1N NaOH (3 mL) was added. The mixture was stirred at RTunder N₂ for 30 min. Aqueous HCl was added to the reaction mixture untilpH 5. The precipate formed was filtered and dried to afford 284 mg ofthe desired product (85%). MS 293.33 (M+H)⁺.

Part D:N-(4-Carbamimidoylphenyl)-3-phenyl-2-(4-phenyl-1H-imidazol-2-yl)propanamidebis-TFA salt

The product from Example 53 from Part C (40 mg, 0.14 mmol) and4-amidinobenzamidine hydrochloride (48 mg, 0.16 mmol) were dissolved inanhydrous pyridine (2 mL). BOP reagent (90 mg, 0.16 mmol) was added andthe reaction was stirred at RT under N₂ for 48 h. The solvent wasremoved in vacuo. The residue was redissolved in CH₃OH/H₂O (9:1)containing 0.1% TFA, and purified by reverse phase HPLC (C18, 28×100 mm,MeOH/H₂O/0.1% TFA gradient) to yield 15 mg of the title compound (17%yield). ¹H NMR (400 MHz, d₄-MeOH) δ 3.33 (dd, J=13.40, 9.45 Hz, 1H),3.52 (dd, J=13.62, 7.03 Hz, 1H), 4.54 (dd, J=9.23, 7.03 Hz, 1H), 7.12(m, 5H), 7.39 (m, 3H), 7.57 (d, J=6.59 Hz, 2H), 7.70 (m, 3H), 7.76 (m,2H). HRMS (M+H)⁺ for C₂₅H₂₄N₅O, calcd m/z: 410.1981, obs: 410.2001.

Example 54N-(3-Carbamimidoylphenyl)-3-phenyl-2-(4-phenyl-1H-imidazol-2-yl)propanamide,Bis-trifluoroacetic acid salt

The title compound was prepared using the same procedures described forExample 53. NMR (400 MHz, d₄-MeOH) δ 3.42 (dd, J=13.62, 9.23 Hz, 1H),3.61 (dd, J=13.62, 7.03 Hz, 1H), 4.61 (dd, J=9.01, 7.25 Hz, 1H), 7.24(m, 5H), 7.51 (m, 5H), 7.66 (d, J=7.91 Hz, 2H), 7.77 (m, 2H), 8.19 (s,1H); MS 410.20, (M+H)⁺.

Example 55trans-N-(4-(Aminomethyl)cyclohexyl)-3-phenyl-2-(4-phenyl-1H-imidazol-2-yl)propanamide,bistrifluoroacetic acid salt

Part A: Benzyl (trans-4-aminocyclohexyl)methylcarbamate

t-Butyl trans-4-aminomethylcyclohexylcarbamate (344 mg, 1.5 mmol) wasdissolved in CH₂Cl₂ (7 mL) and cooled in an ice-bath. Triethylamine(0.21 mL, 1.5 mmol) was added, followed by benzyl chloroformate (0.22mL, 1.5 mmol) dropwise. The mixture was stirred at rt under N₂ for 2 h.The reaction mixture was diluted with CH₂Cl₂ and washed with water andbrine, dried over Na₂SO₄, filtered, and concentrated to a white solid.This solid was dissolved in 10 mL of 4 N HCl-dioxane and stirred at rtfor 10 min. The solvent was removed. The residue was dried under vacuumto give 350 mg of the desired product as a white solid (78%). MS 263.36(M+H)⁺.

Part B: Benzyl(trans-4-(3-phenyl-2-(4-phenyl-1H-imidazol-2-yl)propanamido)cyclohexyl)methylcarbamate

The product from Example 55 Part A (75 mg, 0.25 mmol) and the productfrom Example 53 Part C (60 mg, 0.21 mmol) were dissolved in anhydrouspyridine (5 mL). BOP reagent (115 mg, 0.26 mmol) was added and thereaction was stirred at RT under N₂ for 4 h. The solvent was removed invacuo. The residue was re-dissolved in EtOAc, washed with water andbrine, dried over Na₂SO₄, concentrated and purified by flashchromatography (EtOAc/hexane) to yield 50 mg of the desired product(44%). MS 537.32 (M+H)⁺.

Part C:N-(trans-4-(aminomethyl)cyclohexyl)-3-phenyl-2-(4-phenyl-1H-imidazol-2-yl)propanamide,Bis-trifluoroacetic acid salt

The product from Example 55 Part B (50 mg, 0.093 mmol) was dissolved inMeOH (8 mL) and a catalytic amount of 10% Pd/C was added. The mixturewas placed under 1 atm of H₂ for 4 h. It was filtered through CELITE®and washed with MeOH. The filtrate was concentrated and purified byreverse phase HPLC to give 33 mg of the title compound (56%). ¹H NMR(400 MHz, d₄-MeOH) δ 0.92-1.22 (m, 4H), 1.59 (m, 1H), 1.70-1.88 (m, 4H),2.69 (m, 2H), 3.21 (m, 1H), 3.35 (m, 1H), 3.50 (m, 1H), 4.32 (t, J=8.35Hz, 1H), 7.12-7.32 (m, 5H), 7.38-7.54 (m, 3H), 7.66 (d, J=7.03 Hz, 2H),7.75 (s, 1H). MS 403.39 (M+H)⁺.

Example 564-(2-(1-(4-Carbamimidoylphenylamino)-1-oxo-3-phenylpropan-2-yl)-1H-imidazol-4-yl)benzamide,bis-trifluoroacetic acid salt

Part A: Methyl 2-(4-(4-cyanophenyl)-1H-imidazol-2-yl)-3-phenylpropanoate

2-Benzyl-3-methoxy-3-oxopropanoic acid from Example 53 Part A (5.0 g,24.0 mmol) was dissolved in EtOH (40 mL) and a solution of Cs₂CO₃ (4.0g, 12.0 mmol) in H₂O (40 mL) was added. The reaction mixture was stirredat rt for 1 h under N₂. The solvent was removed under vacuum and theresulting salt was suspended in DMF (85 mL).4-(2-bromoacetyl)benzonitrile (5.4 g, 24.0 mmol) was added in a singleportion and the reaction stirred at rt under N₂ for 4 h. The reactionwas filtered to remove CsBr. The solids were washed with DMF. Thecombined washings and filtrate were concentrated in vacuos to yield ayellow solid. The crude intermediate was placed in a flask fitted with aDean-Stark trap and dissolved in xylene (200 mL). NH₄OAc (38.9 g, 500mmol) was added to the flask and the reaction was heated to reflux for 3h. The reaction was cooled to rt and the solvent removed in vacuo. Theresidue was redissolved in EtOAc and washed with saturated aqueousNaHCO₃ and brine, dried over Na₂SO₄, filtered, concentrated, andpurified by flash chromatography (silica gel, EtOAc/hexane) to yield 2.4g of desired product (30%). MS 332.27 (M+H)⁺.

Part B: 2-(4-(4-Carbamoylphenyl)-1H-imidazol-2-yl)-3-phenylpropanoicacid

The product from Example 56 Part A (0.99 g, 3.0 mmol) was dissolved in10 mL of DMSO. Potassium carbonate (1.24 g, 9.0 mmol) was added. Themixture was cooled to 0-5° C. and 30% H₂O₂ (3.18 mL of 30% aqueoussolution) was added, followed by magnesium oxide (0.24 g, 15 mmol). Thecooling bath was removed and the mixture was stirred at RT under N₂ for4 h. The mixture was filtered to remove inorganic material. Water (30mL) was added to the filtrate and the resulting mixture was stirred atrt for 40 min. The mixture was acidified with 1N HCl to pH 5. Theprecipitate formed was filtered and dried to afford 0.67 g of the acid(67%). MS 336.30 (M+H)⁺.

Part C:4-(2-(1-(4-Carbamimidoylphenylamino)-1-oxo-3-phenylpropan-2-yl)-1H-imidazol-4-yl)benzamide,bis-trifluoroacetic acid salt

The acid from Example 56 Part B (55 mg, 0.16 mmol) and4-amidinobenzamidine hydrochloride (58 mg, 0.34 mmol) were dissolved inanhydrous pyridine (3 mL). BOP reagent (108 mg, 0.24 mmol) was added andthe reaction was stirred at RT under N₂ for 48 h. The solvent wasremoved in vacuo. The residue was redissolved in CH₃OH/H₂O (9:1)containing 0.1% TFA, and purified by reverse phase HPLC (MeOH/H₂O/0.1%TFA gradient) to yield 11 mg of the title compound (10%). ¹H NMR (400MHz, d₄-MeOH) δ 3.34 (m, 1H), 3.49 (m, 1H), 4.29 (t, J=7.91 Hz, 1H),7.17 (m, 1H), 7.22 (m, 4H), 7.56 (s, 1H), 7.78 (m, 6H), 7.89 (m, 2H).HRMS (M+H)⁺ for C₂₆H₂₅N₆O₂, calcd m/z: 453.2039, obs: 453.2025.

Example 574-(2-(1-(1-Aminoisoquinolin-6-ylamino)-1-oxo-3-phenylpropan-2-yl)-1H-imidazol-4-yl)benzamide,bis-trifluoroacetic acid salt

2-(4-(4-Carbamoylphenyl)-1H-imidazol-2-yl)-3-phenylpropanoic acid fromExample 56 Part B (36 mg, 0.11 mmol) and tert-butyl6-aminoisoquinolin-1-ylcarbamate (18 mg, 0.050 mmol) were dissolved inanhydrous pyridine (3 mL). BOP reagent (50 mg, 0.11 mmol) was added andthe reaction was stirred at 60° C. under N₂ for 3 h and then at rt for48 h. The solvent was removed in vacuo. The residue was redissolved inEtOAc (1 mL) and 4N HCl-dioxane (1 mL) and stirred at rt for 1.5 h. Themixture was concentrated and then re-dissolved in CH₃OH/H₂O (9:1)containing 0.1% TFA, and purified by reverse phase HPLC (MeOH/H₂O/0.1%TFA gradient) to yield 6.0 mg of the title compound (17%). ¹H NMR (400MHz, MeOH-d₄) δ 3.45 (m, 1H), 3.63 (m, 1H), 4.62 (dd, J=7.03 Hz, 1H),7.14 (d, J=7.03 Hz, 1H), 7.26 (m, 5H), 7.53 (d, J=7.03 Hz, 1H), 7.79 (d,J=8.35 Hz, 2H), 7.85 (dd, J=9.23, 2.20 Hz, 1H), 7.90 (s, 1H), 7.99 (d,J=8.35 Hz, 2H), 8.33 (d, J=1.76 Hz, 1H), 8.38 (d, J=8.79 Hz, 1H). MS477.3 (M+H)⁺.

Example 584-(2-(1-(Isoquinolin-6-ylamino)-1-oxo-3-phenylpropan-2-yl)-1H-imidazol-4-yl)benzamide,bis-trifluoroacetic acid salt

The title compound was prepared using the same methods described inExample 57. MS 462.19 (M+H)⁺. ¹H-NMR (400 MHz, MeOH-d₄) δ 3.36 (d,J=7.47 Hz, 1H), 3.51 (d, J=8.35 Hz, 1H), 4.31 (t, J=7.91 Hz, 1H), 7.15(m, 1H), 7.23 (d, J=6.59 Hz, 4H), 7.54 (s, 1H), 7.65 (dd, J=8.79, 2.20Hz, 2H), 7.74 (d, J=6.15 Hz, 1H), 7.80 (d, J=8.79 Hz, 2H), 7.89 (m, 2H),8.03 (d, J=9.23 Hz, 1H), 8.35 (m, 1H), 9.10 (s, 1H).

Example 594-(2-(4-(4-Carbamimidoylphenyl)-1H-imidazol-2-yl)-3-phenylpropanamido)benzamide,bis-trifluoroacetic acid salt

Part A: 2-(4-(4-Cyanophenyl)-1H-imidazol-2-yl)-3-phenylpropanoic acid

Methyl 2-(4-(4-cyanophenyl)-1H-imidazol-2-yl)-3-phenylpropanoate fromExample 56 Part A (60 mg, 0.20 mmol) was dissolved in 4 mL of EtOH. NaOH(1.5 mL of 1N aqueous solution) was added and the mixture was stirred RTfor 1.5 h. The mixture was acidified with 1N HCl to pH 5. Theprecipitate formed was filtered and dried to give 40 mg of the acid(63%). MS 318.3 (M+H)⁺.

Part B:4-(2-(4-(4-Cyanophenyl)-1H-imidazol-2-yl)-3-phenylpropanamido)benzamide

The acid from Example 59 Part A (100 mg, 0.32 mmol), triethylamine (150μL, 1.2 mmol), and BOP reagent (210 mg, 0.48 mmol) were dissolved in THF(9 mL). The mixture was stirred at rt for 15 min and 4-aminobenzamide(47 mg, 0.35 mmol) was added. The resulting mixture was heated at 70° C.under N₂ for 1 h. The mixture was concentrated and then re-dissolved inEtOAc. It was washed with water and brine, dried over Na₂SO₄,concentrated, and purified by flash chromatography (silica gel,EtOAc/hexane) to give 45 mg of the desired product (32%). MS 436.3(M+H)⁺.

Part C:4-(2-(4-(4-Carbamimidoylphenyl)-1H-imidazol-2-yl)-3-phenylpropanamido)benzamide,bis-trifluoroacetic acid salt

Hydroxylamine hydrochloride (72 mg, 1.0 mmol) was dissolved in DMSO (1mL) and triethylamine (0.14 mL, 10 eq) was added. The mixture wasstirred for 5 min and the precipitate was filtered off. The filtrate wasadded to the product from Example 59 Part B (28 mg, 0.064 mmol) and themixture was stirred at rt for 15 min, then 4-aminobenzamide (47 mg, 0.35mmol) was added. The resulting mixture was heated at 65° C. under N₂ for1.5 h. It was cooled and water was added. The precipitate formed wasfiltered and dried. The solid was then dissolved in CH₂Cl₂ (3 mL) andacetic anhydride (13 μL) was added. The mixture was stirred at rt underN₂ for 1.5 h. The CH₂Cl₂ was removed and the residue was dissolved inMeOH—HOAc (3 mL of 10:1 solution). Pd/C (10%, 18 mg) was added and themixture was placed under a balloon of hydrogen for 3 h. It was filteredthrough CELITE®, concentrated, then re-dissolved in CH₃OH/H₂O (9:1)containing 0.1% TFA, and purified by reverse HPLC (MeOH/H₂O/0.1% TFAgradient) to yield 8.0 mg of the title compound (18%). ¹H NMR (400 MHz,MeOH-d₄) δ 3.37 (m, 1H), 3.45 (m, 1H), 4.24 (t, J=7.91 Hz, 1H), 7.16 (m,1H), 7.22 (m, 4H), 7.62 (d, J=8.79 Hz, 3H), 7.80 (m, 4H), 7.94 (d,J=8.79, 2H). MS 453.4 (M+H)⁺.

Example 604-(2-(1-(4-Carbamimidoylbenzylamino)-1-oxo-3-phenylpropan-2-yl)-1H-imidazol-4-yl)benzamide,bis-trifluoroacetic acid salt

The acid from Example 56 Part B was coupled with 4-cyanobenzylaminefollowing the procedure of Example 59 Part B. The cyano group was thenconverted to the corresponding benzamidine using the procedures ofExample 59 Part C. MS 467.22 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 3.37(dd, J=13.62, 8.35 Hz, 1H), 3.53 (m, 1H), 4.37 (d, J=15.82 Hz, 1H), 4.55(m, 2H), 7.22 (m, 2H), 7.29 (m, 5H), 7.71 (d, J=8.35 Hz, 2H), 7.79 (d,J=8.79 Hz, 2H), 7.91 (s, 1H), 7.99 (d, J=8.35 Hz, 2H).

Example 61N-(4-Carbamimidoylphenyl)-4-phenyl-3-(4-phenyl-1H-imidazol-2-yl)butanamide,Bis-trifluoroacetic acid salt

This compound was prepared following the same procedures described inExample 53 using 2-benzylsuccinic acid as the starting material. MS424.21 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 3.107 (d, J=3.95 Hz, 1H),3.15 (m, 1H), 3.25 (dd, J=13.40, 6.37 Hz, 1H), 3.95 (m, 1H), 7.12 (d,J=6.95 Hz, 2H), 7.25 (m, 3H), 7.46 (m, 3H), 7.61 (d, J=7.03 Hz, 2H),7.69 (s, 1H), 7.75 (m, 4H).

Example 624-(Aminomethyl)-N—((S)-1-(4-(3-methoxyphenyl)-1H-imidazol-2-yl)-2-phenylethyl)cyclohexane-carboxamide,bistrifluoroacetic acid salt

Part A: (S)-tert-Butyl 1-(1H-imidazol-2-yl)-2-phenylethylcarbamate

(S)-tert-Butyl 1-oxo-3-phenylpropan-2-yl carbamate (5.08 g, 20.4 mmol)and glyoxal trimeric dihydrate (2.2 g, 10.1 mmol) were dissolved inanhydrous MeOH (30 mL). Ammonia in methanol (2.0 M, 45.6 mL, 92.4 mmol)was added and the reaction was stirred for 48 h at rt. The solvent wasremoved under vacuum. The resulting oil was diluted with EtOAc, washedwith brine, dried over MgSO₄, filtered and evaporated in vacuo to yield1.4 g (47%) of white solid. MS 288.15 (M+H)⁺.

Part B: (S)-tert-Butyl1-(4,5-dibromo-1H-imidazol-2-yl)-2-phenylethylcarbamate

The product from Example 62 Part A (510 mg, 1.8 mmol) was dissolved inchloroform (10 mL) and treated with NBS (600 mg, 3.38 mmol) at rt. Thereaction was stirred for 1 h. The solvent was removed under vacuum andthe crude product purified using silica gel chromatography to yield 510mg (64%) of a white solid. MS 445.91 (M+H)⁺.

Part C: (S)-tert-Butyl1-(4-bromo-1H-imidazol-2-yl)-2-phenylethylcarbamate

The product from Example 62 Part B (821 mg, 2.38 mmol) was dissolved inmixture of 1,4 dioxanes (8 ml) and water (2 mL). Sodium sulfite (3.00 g,23.8 mmol) and tetrabutylammonium hydrogensulfate (2.01 g, 5.95 mmol)were added. The reaction was heated at 100° C. for 48 h. The reactionwas diluted with EtOAc and the solids were filtered off. The filtratewas washed with brine, dried over MgSO₄, filtered and evaporated todryness. The crude was purified by silica gel chromatography to provide200 mg (24%) of a white solid. MS 366.3 (M+H)⁺.

Part D: (S)-1-(4-Bromo-1H-imidazol-2-yl)-2-phenylethanamine

The product from Example 62 Part C (560 mg, 1.53 mmol) was treated withTFA according to the procedure described for Example 1 Part B to provide490 mg of the crude product as a yellow oil that contained excess TFA.The crude product was used in the next reaction without furtherpurification. MS 268.3 (M+H)⁺.

Part E: tert-Butyl((1S,4r)-4-(((S)-1-(4-bromo-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)cyclohexyl)methylcarbamate

The product from Example 62 Part D (494 mg, 1.86 mmol) andN-Boc-tranexamic acid (480 mg, 1.8 mmol) were treated using theconditions described in Example 2 Part A. The resulting white solid (780mg, 83%) was carried to the next step without further purification. MS503.28 (M+H)⁻.

Part F: tert-Butyl((1S,4r)-4-(((S)-1-(4-(3-methoxyphenyl)-1H-imidazol-2-yl)-2-phenylethyl)carbamoyl)cyclohexyl)methylcarbamate

The product from Example 62 Part E (30.0 mg, 0.059 mmol) was weighedinto a vial containing 3-methoxyphenyl boronic acid (11 mg, 0.07 mmol)and K₃PO₄ (38 mg, 0.177 mmol). The solids were dissolved in 1,4 dioxanes(0.5 mL). Palladium (I) tri tert-butyl phosphine bromide dimer (19 mg,0.024 mmol) was added, and the vial was sealed under argon. The reactionwas heated using microwave irradiation at 110° C. for 1 hr. The reactionwas cooled to rt, and the solids filtered off. The filtrate wascollected and dried under vacuum. The crude product, contaminated withstarting material, was carried forward to next step. MS 433.22 (M+H)⁺.

Part G:4-(Aminomethyl)-N—((S)-1-(4-(3-methoxyphenyl)-1H-imidazol-2-yl)-2-phenylethyl)cyclohexane-carboxamide,bistrifluoroacetic acid salt

The product from Example 62 Part F (30 mg, 0.059 mmol) was treated withTFA according to the procedure described for Example 1 Part B. Theproduct was isolated by prep HLPC to yield 6.00 mg (24%) of as the titlecompound. ¹H NMR (500 MHz, d₄-MeOH) δ 1.07 (m, 2H) 1.16 (dd, J=12.37,3.57 Hz, 1H) 1.27 (d, J=15.40 Hz, 1H) 1.39 (m, 2H) 1.57 (m, 2H) 1.80 (d,J=12.10 Hz, 1H) 1.86 (d, J=11.00 Hz, 3H) 1.94 (d, J=11.00 Hz, 1H) 2.26(m, 2H) 2.77 (d, J=7.15 Hz, 2H) 2.83 (d, J=7.15 Hz, 1H) 3.37 (m, 1H)3.78 (s, 1H) 3.85 (s, 3H) 5.30 (t, J=8.25 Hz, 1H) 6.63 (m, 1H) 6.81 (m,1H) 6.81 (m, 1H) 7.19 (m, 4H) 7.24 (t, J=7.42 Hz, 1H) 7.28 (m, 3H) 7.39(m, 1H) 7.76 (s, 1H): MS 433.22 (M+H)⁺.

Examples 63 to 65 and 89 listed in Table 2 were similarly synthesized byappropriate application of the procedures described for Example 62 or bystraightforward extension of those procedures by one skilled in the art.

Example 66trans-3-(2-((S)-1-(4-(Aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)-benzoicacid, bistrifluoroacetic acid salt

The product from Example 7 (85 mg, 0.18 mmol) was hydrolyzed accordingto the procedure described for Example 26. The crude product wasre-dissolved in MeOH/H₂O (9:1) containing 0.1% TFA and evaporated todryness to yield 86 mg (71%) of the title compound. ¹H NMR (500 MHz,CDCl₃) δ 0.92 (m, 2H), 1.18 (m, 2H), 1.48 (m, 1H), 1.64 (d, J=12.60 Hz,1H), 1.77 (d, J=11.00 Hz, 3H), 2.15 (t, J=12.10 Hz, 1H), 2.61 (m, 2H),3.23 (m, 1H), 3.42 (m, J=5.50 Hz, 1H), 5.37 (bs, 1H), 7.21 (t, J=6.32Hz, 1H), 7.27 (m, 3H), 7.63 (t, J=7.42 Hz, 1H), 8.00 (m, 3H), 8.15 (d,J=6.60 Hz, 1H), 8.39 (s, 1H); HRMS (M+H)⁺ for C₂₆H₃₀N₄O₃, calcd m/z:447.2396, obs: 447.2407.

Examples 67 and 68 Methyl4-(2-((S)-1-(trans-4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)benzoate,bis-trifluoroacetic acid salt (67), and4-(2-((S)-1-(trans-4-(Aminomethyl)cyclohexane-carboxamido)-2-phenylethyl)-1H-imidazol-4-yl)benzoicacid, bis-trifluoroacetic acid salt (68)

Part A: (S)-Ethyl4-(2-(1-(tert-butoxycarbonyl)-2-phenylethyl)-1H-imidazol-4-yl)benzoate

The product (8.5 g, 97% over two steps) was synthesized fromL-N-(Boc)-phenylalanine (3.99 g, 20 mmol), Cs₂CO₃ (3.25 g, 10 mg), ethyl4-(2-bromoacetyl)benzoate (5.4 g, 20 mmol) and ammonium acetate (31 g,400 mmol) by appropriate application of the conditions described forExample 1 Part A. MS 436.1 (M+1)⁺.

Part B: Ethyl4-(2-((S)-1-(trans-4-(aminomethyl)cyclohexanecarboxamido)-2-phenylethyl)-1H-imidazol-4-yl)benzoate,bistrifluoroacetic acid salt

The product from Part A (220 mg, 0.48 mmol) was treated sequentiallyaccording to the procedures for Example 1 Part B, and Example 2 Part Aand Part B to provide 200 mg of product (56% over three steps). MS 334.2(M−H)⁻.

Part C: Example 67 and 68

The product from Part B (200 mg, 0.28 mmol) was dissolved in MeOH/H₂O(9:1) containing 0.1% TFA (2 mL). The pH of the solution was adjusted to12-14 using 1 N aqueous NaOH. The reaction was stirred at rt for 16 h.TFA was added to the solution until it reached pH=1 and the productswere isolated by prep HPLC to yield 66 mg of Example 67 (34%) and 34 mgof Example 68 (18%).

Data for Example 67: ¹H NMR (500 MHz, d₄-MeOH) δ 1.06 (m, 2H), 1.38 (m,2H), 1.57 (m, 1H), 1.80 (d, J=11.55 Hz, 1H), 1.86 (d, J=11.55 Hz, 3H),2.28 (tt, J=12.10, 3.30 Hz, 1H), 2.77 (d, J=6.60 Hz, 2H), 3.33 (d,J=8.25 Hz, 1H), 3.38 (dd, J=13.20, 8.00 Hz, 1H), 3.93 (s, 3H), 5.33 (t,J=8.25 Hz, 1H), 7.18 (d, J=7.15 Hz, 2H), 7.23 (t, J=7.15 Hz, 1H), 7.29(t, J=7.15 Hz, 2H), 7.77 (d, J=8.80 Hz, 2H), 7.89 (s, 1H), 8.11 (d,J=8.80 Hz, 2H); HRMS (M+H)⁺ for C₂₇H₃₂N₄O₃, calcd m/z: 461.2523, obs:461.2570.

Data for Example 68: ¹H NMR (500 MHz, d₄-MeOH) δ 1.06 (m, 2H), 1.39 (m,2H), 1.57 (m, 1H), 1.80 (d, J=12.10 Hz, 1H), 1.86 (d, J=11.55 Hz, 3H),2.28 (tt, J=12.10, 3.30 Hz, 1H), 2.77 (d, J=7.15 Hz, 2H), 3.33 (d,J=8.25 Hz, 1H), 3.39 (dd, J=13.50, 8.25 Hz, 1H), 5.33 (t, J=8.25 Hz,1H), 7.19 (d, J=7.15 Hz, 2H), 7.24 (t, J=7.15 Hz, 1H), 7.29 (t, J=7.15Hz, 2H), 7.76 (d, J=8.25 Hz, 2H), 7.89 (s, 1H), 8.12 (d, J=8.80 Hz, 2H);HRMS (M+H)⁺ for C₂₆H₃₀N₄O₃, calcd m/z: 447.2396, obs: 447.2397.

Example 69trans-N—((S)-1-(4-(3-Amino-1H-indazol-6-yl)-1H-imidazol-2-yl)-2-phenylethyl)-4-(aminomethyl)-cyclohexanecarboxamide,bistrifluoroacetic acid salt

The product from Example 65 (10 mg, 0.022 mmol) was dissolved in1-butanol. Hydrazine (66 mg, 1.32 mmol) was added and the reactionmixture was heated to 118° C. using microwave irradiation in a sealedtube for 4.5 h. The reaction was cooled to rt and stirred for anadditional 8 h. The solvent and excess hydrazine were removed in vacuo.The product was re-dissolved in MeOH/H₂O (9:1) containing 0.1% TFA. Thesolvent was removed under vacuum to provide the title compound (8.8 mg,59%). HRMS (M+H)⁺ for C₂₆H₃₁N₇O, calcd m/z: 458.2668, obs: 458.2650.

Example 70trans-4-(Aminomethyl)-N-benzyl-N—((S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethyl)cyclohexanecarboxamide,bistrifluoroacetic acid salt

Part A: (S)—N—Benzyl-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

The product from Example 1 Part B (33 mg, 0.1 mmol) and benzaldehyde (16mg, 0.15 mmol) were dissolved in CH₂Cl₂ (4 mL). NaBH(OAc)₃ (32 mg, 0.15mmol) was added, followed by a few drops of HOAc. The reaction wasstirred at rt for 48 h. The reaction was diluted with CH₂Cl₂ and washedwith water and brine. It was dried over Na₂SO₄, filtered and evaporatedin vacuo to give 42 mg, of the crude product. MS 354.5 (M+H)⁺.

Part B:trans-4-(Aminomethyl)-N-benzyl-N—((S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethyl)cyclohexanecarboxamide,bistrifluoroacetic acid sal

The product from Example 70 Part A was converted to the title compoundfollowing the same procedures described in Example 2 Part A-B. ¹H NMR(500 MHz, d₄-MeOH) δ 0.95 (m, 2H), 1.25 (m, 1H), 1.60 (m, 3H), 1.80 (m,3H), 2.49 (t, J=8.52 Hz, 1H), 2.72 (d, J=7.15 Hz, 2H), 3.53 (d, J=3.30Hz, 2H), 4.80 (m, 2H), 6.14 (t, J=8.25 Hz, 1H), 7.00-7.53 (m, 16H). MS493.20 (M+H)⁺.

Examples 71 to 74 and Example 85 listed in Table 5 were synthesized byappropriate application of the procedures described for Example 70 or bystraightforward extension of the procedures described for Example 70 byone skilled in the art.

Example 77 trans-4-Aminomethyl-cyclohexanecarboxylic acid[2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amide, bistrifluoroaceticacid salt

Part A:{4-[2-Phenyl-1-(4-phenyl-1H-imidazol-2-yl)-ethylcarbamoyl]-cyclohexyl-methyl-carbamicacid phenyl ester

The product from Example 55 Part A (36 mg, 0.1 mmol) was dissolved inTHF/DMF (2:1, 6 mL) and cooled to 0° C. Dicyclohexyl-carbodiimide (162mg, 0.1 mmol) was added to the solution. The resulting mixture wasstirred at 0° C. for 1 h. The product from Example 1 Part B (33 mg, 0.1mmol) was added, and the reaction was warmed to 50° C. for 5 h. Thereaction was cooled to rt, diluted with EtOAc, washed with water andbrine (3×), dried over Na₂SO₄, filtered, and dried in vacuo. The titlecompound was isolated by preparative HPLC to yield 27 mg (40%) as acolorless solid. MS 552.1 (M+H)⁺.

Part B: 4-Aminomethyl-cyclohexanecarboxylic acid[2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amide

The product from Example 77 Part A (27 mg, 0.04 mmol) was converted tothe final product (16 mg, 75%) using the procedure described for Example50 Part C. ¹H NMR (500 MHz, d₄-MeOH) δ 1.09 (m, 2H), 1.19 (m, 2H), 1.57(m, 1H), 1.81 (m, 2H) 1.92 (m, 2H), 2.76 (d, J=6.60 Hz, 2H), 3.25 (m,1H), 3.35 (m, 2H), 5.21 (t, J=7.42 Hz, 1H), 7.16 (d, J=7.15 Hz, 2H),7.24-7.29 (m, 3H), 7.44-7.49 (m, 3H), 7.65 (d, J=8.24 Hz, 2H), 7.72 (s,1H). MS 418.1 (M+1)⁺.

Example 82(S)-4-[2-[1-[4-(Aminomethyl)cyclohexanecarboxamido]amino]-2-phenylethyl]-4-(bromo-1H-imidazol-5-yl)-benzamidePart A:(4-{1-[5-Bromo-4-(4-carbamoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethylcarbamoyl}-cyclohexylmethyl)-carbamicacid tert-butyl ester

The product from Example 28 Part A (70 mg, 0.13 mmol) was dissolved inCHCl₃ (10 mL) and treated with bromine (21 mg, 0.13 mmol). Afterstirring for 16 h, the reaction was evaporated to dryness in vacuo toyield 93 mg (>99%) of product. MS 625.3/627.3 (1:1; M+H)⁺.

Part B:4-(2-{1-[(4-Aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-5-bromo-1H-imidazol-4-yl)-benzamide

The crude product from Example 82 Part A (93 mg, 0.13 mmol) wasconverted to the title compound (35.8 mg, 36%) using the proceduredescribed for Example 2 Part B. ¹H NMR (500 MHz, d₄-MeOH) δ 1.38 (m, 1H)1.57 (m, 1H) 1.76 (d, J=12.65 Hz, 1H) 1.85 (d, J=9.90 Hz, 3H) 2.23 (dt,J=12.10, 3.30 Hz, 1H) 2.77 (d, J=7.15 Hz, 2H) 3.20 (dd, J=13.20, 8.25Hz, 1H) 3.26 (dd, J=13.30, 7.70 Hz, 1H) 5.23 (t, J=7.97 Hz, 1H) 7.17 (d,J=7.15 Hz, 2H) 7.21 (d, J=7.15 Hz, 1H) 7.26 (t, J=7.15 Hz, 2H) 7.75 (d,J=8.80 Hz, 2H) 7.95 (d, J=8.80 Hz, 2H). MS 524.3/526.3 (1:1; M+H)⁺.

Example 107(S)-4-[2-[1-[4-(Aminomethyl)cyclohexanecarboxamido]-2-phenylethyl]-4-(trifluoromethyl)-1H-imidazol-5-yl]-benzamide,bis-trifluoroacetic acid salt Part A:trans-{4-[(S)-1-(4-Bromo-5-trifluoromethyl-1H-imidazol-2-yl)-2-phenyl-ethylcarbamoyl]-cyclohexylmethyl}-carbamicacid tert-butyl ester

The product from Part A of Example 32 was converted to the titlecompound by sequential application of the procedures described forExample 1 Part B, Example 2 Part A and Example 82 Part A. MS:573.3/575.3 (M+1)⁺.

Part B:trans-(4-{(S)-1-[4-(4-Carbamoyl-phenyl)-5-trifluoromethyl-1H-imidazol-2-yl]-2-phenyl-ethylcarbamoyl}-cyclohexylmethyl)-carbamicacid tert-butyl ester

The product from Example 107 Part A (47 mg, 0.069 mmol),4-carbamoylphenyl-boronic acid (30 mg, 0.18 mmol), K₃PO₄ (75 mg, 0.35mmol), and Pd(PPh₃)₄ (22 mg) were added together with 6 mL of1,4-dioxane. The mixture was heated in a sealed tube in the microwave at110° C. for 1.5. h. The solvent was removed. The residue was dissolvedin EtOAc and washed with water and brine. It was dried over MgSO₄,concentrated, and purified by flash chromatography (silica,EtOAc/hexane) to give 25 mg of the desired product. MS: 614.4 (M+1)⁺.

Part C:trans-4-(2-{(S)-1-[(4-Aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-5-trifluoromethyl-1H-imidazol-4-yl)-benzamide,bis-trifluoroacetic acid salt

The product from Example 107 Part B was converted to Example 107 (15 mg)by the appropriate application of the procedure described for Example 2Part B. MS: 514.3 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 1.04 (m, 2H), 1.39(m, 2H), 1.57 (m, 1H), 1.82 (m, 4H), 2.21 (m, 1H), 2.76 (d, J=7.03 Hz,2H), 3.20 (m, 2H), 5.25 (m, 1H), 7.20 (m, 5H), 7.50 (d, J=8.35 Hz, 2H),7.93 (d, J=8.79 Hz, 2H).

Example 108N—{(S)-1-[4-(4-Carbamimidoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-benzamide

Hydroxylamine hydrochloride (10 eq) was dissolved in DMSO (1 mL) andtriethylamine (10 eq) added. The mixture was stirred for 5 min thenfiltered to remove triethylamine hydrochloride. The compound of Example178 Part A (80 mg) was added to the filtrate and the mixture was heatedat 65° C. for 1-1.5 h. Reaction was cooled to room temperature, dilutedwith ˜10 mL water, and resulting precipitate collected, washed withwater and dried to give the amidoxime intermediate (73 mg, 84%). m/z426.4 (M+H)⁺. This material was suspended in methylene chloride (10 mL)and acetic anhydride (0.040 mL) was added. The mixture was stirred for20 min at room temperature under Argon then evaporated to dryness. Theresidue was dissolved in a mixture of methanol/HOAc (10:1), 10% Pd/C wasadded and the mixture was stirred under 1 atm H₂ for 2 h. Catalyst wasremoved by filtration, filtrate evaporated and residue purified by prepC18 HPLC to provide the bis TFA salt of the title compound (65 mg,60%)¹H NMR (400 MHz, MeOH-d₄) δ 3.41-3.59 (m, 2H) 5.53 (t, J=8.13 Hz,1H) 7.20-7.31 (m, 5H) 7.46 (t, J=7.69 Hz, 2H) 7.56 (t, J=7.47 Hz, 1H)7.84 (d, J=7.03 Hz, 2H) 7.87-7.95 (m, 5H) m/z 410.2 (M+H)⁺.

Example 109trans-S-(2-{(S)-1-[(4-Aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-1H-imidazol-4-yl)-2-cyano-benzoicacid, bistrifluoroacetic acid salt Part A: 5-Acetyl-2-cyano-benzoic acidmethyl ester

Triflic anhydride (10 g, 35.4 mmol) was added dropwise to a cold (−40°C.) solution of 5-acetyl-2-hydroxy-benzoic acid methyl ester (6.9 g,35.4 mmol) and DIPEA (5.3 g, 42.5 mmol) in CH₂Cl₂ (100 mL). The reactionwas warmed to −10° C. and stirred for 16 h. The reaction was warmed tort, evaporated to dryness in vacuo, and re-dissolved in EtOAc. Theorganic layer was washed with ½ sat. brine, dried over MgSO₄, filteredand evaporated in vacuo. A portion of the crude triflate (5.01 g, 15.3mmol) was dissolved in DMF (40 mL). Palladium (0)tetrakis(triphenylphosphine) (1.3 g, 1.1 mmol) and zinc cyanide (2.16 g,18.4 mmol) were added to the flask, and the mixture was heated to 90° C.for 2.5 h. The reaction was cooled to rt and stirred with a 1:1 solutionof conc. NH₄OH and water (160 mL). The resulting suspension wasextracted with ETOAc. The combined organic extracts were washed with ½sat. brine, dried over MgSO₄, filtered and evaporated in vacuo. Thetitle compound was isolated by SiO₂ chromatography to yield 439 mg (14%)of a white solid. MS 221.1 (M+NH₄)⁺.

Part B: 5-(2-Bromo-acetyl)-2-cyano-benzoic acid methyl ester

The product from Example 109 Part A (107 mg, 0.53 mmol) was dissolved inCH₂Cl₂ (5 mL) and treated with bromine (84 mg, 0.53 mmol). The solutionchanged color from rust red to yellow after 3 h indicating the reactionwas complete. The reaction was diluted with CH₂Cl₂, washed with sat'dNaHCO₃, dried over Na₂SO₄, filtered and evaporated in vacuo to yield 160mg (>99%) of a colorless solid. ¹H NMR (500 MHz, CDCl₃) δ 4.05 (s, 3H)4.47 (s, 2H) 7.97 (d, J=7.70 Hz, 1H) 8.26 (m, 1H) 8.69 (s, 1H).

Part C:(S)-2-{[4-(tert-Butoxycarbonylamino-methyl)-cyclohexanecarbonyl]-amino}-3-phenyl-propionicacid

4-(tert-Butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (1.7 g,6.6 mmol) and ethyl phenylalanine hydrochloride (2.0 g, 6.6 mmol) weredissolved in DMF (30 mL) and combined with HOAt (0.5 M in DMF, 16 mL, 8mmol) and 4-methylmorpholine (2.33 g, 23 mmol). To this mixture wasadded EDCI (1.76 g, 9.2 mmol). The reaction was stirred at rt for 12 h,diluted with EtOAc, washed several times with ½ sat'd brine, dried overMgSO₄, filtered and evaporated in vacuo to yield 2.8 g (99%) of acolorless solid which was dissolved in MeOH (30 mL) and treated with 1 NNaOH (19 mL) at rt for 3 h. The MeOH was removed in vacuo and theresidue redissolved in water. The aqueous solution was acidified with 1N HCl to pH 1 and extracted with EtOAc. The combined organic extractswere dried over MgSO₄, filtered and concentrated in vacuo to yield 2.5 g(95%) of the title compound as the free acid. MS 403.0 (M+H)⁺.

Part D:5-[2-((S)-1-{[4-(tert-Butoxycarbonylamino-methyl)-cyclohexanecarbonyl]-amino}-2-phenyl-ethyl)-1H-imidazol-4-yl]-2-cyano-benzoicacid ethyl ester

The product from Example 109 Part B (149 mg, 0.53 mmol) and the productfrom Example 109 Part D (214 mg, 0.53 mmol) were combined according tothe procedure described for Example 1 Part A to yield 73.6 mg (24%) ofthe title compound. MS 584.4 (M−H)⁻.

Part E:5-(2-{(S)-1-[(4-Aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-1H-imidazol-4-yl)-2-cyano-benzoicacid

The product from Example 109 Part B (149 mg, 0.53 mmol) and the productfrom Example 109 Part D (214 mg, 0.53 mmol) were combined according tothe procedure described for Example 1 Part A to yield 73.6 mg (24%) ofthe title compound. MS 584.4 (M−H⁺)⁻.

Part F:5-(2-{(S)-1-[(4-Aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-1H-imidazol-4-yl)-2-cyano-benzoicacid

The product from Example 109 Part E (13 mg, 0.022 mmol) was dissolved inanhyd. MeOH and cooled to 0° C. Anhyd. ammonia gas was bubbled into thesolution for ca. 15 min, then the reaction vessel was tightly capped andthe reaction stirred for 24 h at rt. The reaction was sparged withnitrogen and evaporated to dryness. The crude product was dissolved in10% TFA in CH₂Cl₂ (v/v) and stirred for 16 h at rt. The solvent and TFAwere evaporated in vacuo. The crude product was re-dissolved in MeOH/H₂O(9:1) containing 0.1% TFA. The title compound was isolated as acolorless glass via preparative HPLC to yield 2.0 mg (19%). ¹H NMR (500MHz, d₄-MeOH) δ 1.06 (m, 2H) 1.39 (m, 2H) 1.57 (m, 1H) 1.79 (d, J=12.10Hz, 1H) 1.86 (d, J=12.10 Hz, 3H) 2.26 (m, 1H) 2.77 (d, J=6.60 Hz, 2H)3.33 (d, J=8.25 Hz, 2H) 5.32 (t, J=7.97 Hz, 1H) 7.19 (d, J=6.60 Hz, 2H)7.22 (m, 1H) 7.28 (t, J=7.15 Hz, 3H) 7.92 (s, 2H) 8.09 (d, J=7.70 Hz,1H) 8.13 (s, 1H). MS 472.3 (M+H⁺)⁺.

Example 113(S)—N-[1-[4-(3-Amino-1H-indazol-6-yl)-5-bromo-1H-imidazol-2-yl]-2-phenylethyl]-4-(aminomethyl)-trans-cyclohexanecarboxamide,bis-trifluoroacetic acid salt

Example 113 was synthesized by appropriate application of the proceduresdescribed in Example 120, except that the procedure for Example 82 PartA was used in place of the procedure for Example 120 Part D. ¹H NMR (500MHz, d₄-MeOH) δ 1.05 (m, 2H) 1.39 (m, 2H) 1.57 (m, 1H) 1.75 (bd, J=12.10Hz, 1H) 1.85 (bd, J=13.20 Hz, 3H) 2.22 (m, 1H) 2.77 (d, J=7.15 Hz, 2H)3.16 (dd, J=13.20, 8.25 Hz, 1H) 3.24 (dd, J=13.20, 7.40 Hz, 1H) 5.21 (t,J=7.97 Hz, 1H) 7.18 (m, 3H) 7.25 (t, J=7.42 Hz, 2H) 7.47 (d, J=9.90 Hz,1H) 7.70 (s, 1H) 7.92 (d, J=8.25 Hz, 1H). MS: 536 (M+H⁺)⁺.

Example 114(S)-5-[4-(Carbamoylphenyl]-2-[1-[4-(aminomethyl)cyclohexanecarboxamido]-2-phenylethyl]-1H-imidazole-4-carboxylicacid, methyl ester, bis-trifluoroacetic acid salt

Part A:2-((S)-1-tert-Butoxycarbonylamino-2-phenyl-ethyl)-3H-imidazole-4-carboxylicacid methyl ester

The compound from Part B of Example 32 (0.42 g, 1.07 mmol) was dissolvedin MeOH (8 mL) and TFA (0.8 mL) was added. The mixture was stirred at RTunder N₂ for 30 minutes. Aqueous NaHCO₃ was added and the MeOH wasremoved. The aqueous was extracted with CH₂Cl₂. The CH₂Cl₂ solution waswashed with brine, dried over MgSO₄, and concentrated to a yellow foam(0.40 g). LC/MS: 346.4 (M+1)⁺.

Part B:5-Bromo-2-((S)-1-tert-butoxycarbonylamino-2-phenyl-ethyl)-3H-imidazole-4-carboxylicacid methyl ester

The product from Example 114 Part A (1.2 g of 83% pure, 0.28 mmol) wasdissolved in CHCl₃ (20 mL) and NBS (0.93 g, 0.41 mmol) was added. Themixture was stirred at RT under N₂ for 1.5 h. It was diluted with CHCl₃and washed with water and brine. It was then dried over MgSO₄ andconcentrated to a white solid (0.79 g). MS: 424.4/426.2 (M+1)⁺.

Part C:trans-5-Bromo-2-((S)-1-{[4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarbonyl]-amino}-2-phenyl-ethyl)-3H-imidazole-4-carboxylicacid methyl ester

The product from Example 114 Part B was converted to the title compoundby sequential application of the procedures described for Example 1 PartB and Example 2 Part A. LC/MS: 563.3 (M+1)⁺.

Part D:trans-2-{(S)-1-[(4-Aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-5-(4-carbamoyl-phenyl)-3H-imidazole-4-carboxylicacid methyl ester, bis-trifluoroacetic acid salt

The product from Example 114 Part C was converted to Example 114 bysequential application of the procedures described for Example 107 PartB and Example 2 Part B. MS: 504.4 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ1.05 (m, 2H), 1.39 (m, 2H), 1.57 (m, 1H), 1.81 (m, 4H), 2.23 (m, 1H),2.77 (d, J=7.03 Hz, 2H), 3.24 (m, 2H), 3.82 (s, 3H), 5.28 (t, J=7.91 Hz,1H), 7.21 (m, 5H), 7.76 (d, J=8.35 Hz, 2H), 7.94 (d, J=8.35 Hz, 2H).

Example 117(S)—N-[1-[4-[4-(Carbamoyl)phenyl]-1H-imidazol-2-yl]-2-phenylethyl]-4-(aminomethyl)-benzamide

This compound was prepared by appropriate application of the methodsdescribed in Example 28. MS: 440.2 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ3.53 (m, 2H), 4.19 (s, 2H), 5.55 (m, 1H), 7.27 (m, 5H), 7.57 (m, 2H),7.77 (m, 2H), 7.80-8.02 (m, 5H).

Example 1184-Aminomethyl-N-{(S)-1-[4-(4-carbamoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-2-fluorobenzamide

Example 118 was prepared by appropriate application of the methodsdescribed in Example 28. MS: 458.2 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ3.47 (dd, J=13.84 and 8.13 Hz, 2H), 4.18 (s, 2H), 5.59 (t, J=7.91 Hz,1H), 7.29 (m, 7H), 7.77 (m, 3H), 7.89 (s, 1H), 7.98 (d, J=8.79 Hz, 2H).

Example 119trans-2-{(S)-1-[(4-Aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-5-(4-carboxy-phenyl)-3H-imidazole-4-carboxylicacid, bis-trifluoroacetic acid salt

The product from Example 114 was hydrolyzed with LiOH/THF to give theExample 119. MS: 491.4 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 1.05 (dd,J=12.52 and 4.17 Hz, 2H), 1.39 (m, 2H), 1.57 (m, 1H), 1.85 (m, 4H), 2.23(m, 1H), 2.77 (d, J=7.03 Hz, 2H), 3.23 (m, 2H), 5.29 (t, J=7.91 Hz, 1H),7.21 (m, 5H), 7.81 (d, J=8.35 Hz, 2H), 8.06 (d, J=8.79 Hz, 2H).

Example 120(S)—N-[1-[4-(3-Amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl]-4-(aminomethyl)-trans-cyclohexanecarboxamide,bis-trifluoroacetic acid salt

Part A: 4-Cyano-3-fluorobenzoic acid

4-Bromo-3-fluorobenzoic acid (7.5 g, 0.034 mol), Zn(CN)₂ (4.0 g, 0.034mol) and Pd(PPh₃)₄ (3.95 g, 0.0034 mol) were added together with 60 mLof DMF (degassed). The mixture was heated at 90° C. under N₂ for 3 h. Itwas cooled to room temperature and filtered to remove insolubleinorganic salts (discarded). The filtrate was diluted with water andextracted with EtOAc. The EtOAc mixture was washed with water, brine,dried over MgSO₄, and concentrated to yield 4.5 g of the desired productwith 90% purity. This material was taken into the next step withoutfurther purification. ¹H NMR (500 MHz, d₄-MeOH) δ 7.82 (m, 1H), 7.90 (m,3H), 7.56 (d, J=10.0 Hz, 1H), 7.68 (s, 1H), 7.96 (d, J=8.4 Hz, 1H).

Part B: 4-(2-Bromoacetyl)-2-fluorobenzonitrile

4-Cyano-3-fluorobenzoic acid (4.0 g of 90% pure material, 0.02 mol) wasdissolved in CH₂Cl₂ (50 mL). To it was added dropwise oxalyl chlorideover 15 minutes (2.3 mL, 0.026 mol). The mixture was stirred at rt for 1h and then heated at reflux for 1 h under N₂. The solvent was removed,and the residue was redissolved in CH₃CN (50 mL). This solution wascooled to −15° C., and to it was added (trimethylsilyl)diazomethane(11.5 mL of 2.0M in hexane) dropwise over 20 minutes. The resultingmixture was stirred at −15° C. for 1 h under N₂. To it was addeddropwise a solution of HBr in HOAc (4.25 mL of 33% wt) over 20 minutes,and the reaction mixture was stirred at −15° C. for 20 minutes. Thesolvent was removed, and the residue was dissolved in EtOAc, washed withwater, brine, dried over MgSO₄, and concentrated to 3.2 g of the desiredproduct. MS: 240.1, 242.1, (M+H)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 2.42 (s,2H), 7.76-7.85 (m, 3H).

Part C: tert-Butyl(S)-1-(4-(4-cyano-3-fluorophenyl)-1H-imidazol-2-yl)-2-phenylethylcarbamate

4-(2-Bromoacetyl)-2-fluorobenzonitrile (3.2 g 0.013 mol),L-Boc-phenylalanine (3.5 g, 0.013 mol), and Cs₂CO₃ (2.6 g, 0.008 mol)were added together with DMF (20 mL). The mixture was stirred at 15° C.for 1 h under N₂. It was diluted with 100 mL of EtOAc, washed withwater, brine, dried over MgSO₄, concentrated, and purified by flashchromatography (120 g×2 silica, 10-55% EtOAc in hexane) to give 3.5 g ofthe desired ester. LC/MS: 425.3. This material was then combined withammonium acetate (12 g) and suspended in xylenes (100 mL). The mixturewas heated under N₂ at 150° C. for 2.5 h in a flask equipped with aDean-Stark trap. The xylenes were removed. The residue was dissolved inEtOAc, and washed with water and brine. It was dried over MgSO₄,concentrated, and purified by flash chromatography (120 g×2 silica,15-70% EtOAc in hexane) to give 2.2 g of the desired imidazole. MS: 407(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 1.39 (s, 9H), 3.30 (m, 2H), 4.86 (d,J=6.59 Hz, 1H), 5.32 (d, J=7.47 Hz, 1H), 7.14-7.24 (m, 6H), 7.53-7.61(m, 3H).

Part D: tert-Butyl(S)-1-(5-chloro-4-(4-cyano-3-fluorophenyl)-1H-imidazol-2-yl)-2-phenylethylcarbamate

The product from Example 120 Part C (2.2 g, 5.4 mmol) andN-chlorosuccinimide (0.80 g, 6.7 mmol) were added together with CH₃CN(100 mL). The mixture was heated at reflux for 7 h under N₂. The solventwas removed, and the residue was dissolved in EtOAc. It was washed withwater, aqueous NaHCO₃, and brine, dried over MgSO₄, and concentrated togive 2.4 g of foam. MS: 441.3, (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 1.27(s, 9H), 3.23 (m, 2H), 4.89 (m, 1H), 5.46 (d, J=7.03 Hz, 1H), 7.07 (d,J=6.15 Hz, 2H), 7.25-7.26 (m, 5H), 7.54 (m, 1H).

Part E:4-(2-((S)-1-Amino-2-phenylethyl)-5-chloro-1H-imidazol-4-yl)-2-fluorobenzonitrile

The product from Example 120 Part D (0.20 g, 0.45 mmol) was stirred withCH₂Cl₂ (6 mL) and TFA (1.5 mL) under N₂ for 0.5 h. The solvents wereremoved. The residue was dried under vacuum to give 0.26 g of thebis-TFA salt. MS: 340.94, (M+H)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 3.33 (m,2H), 4.56 (dd, J=8.57, 6.37 Hz, 1H), 7.12 (d, J=6.59 Hz, 2H), 7.25-7.30(m, 3H), 7.67 (m, 2H), 7.81 (m, 1H).

Part F:trans-(4-{(S)-1-[5-Chloro-4-(4-cyano-3-fluoro-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethylcarbamoyl}-cyclohexylmethyl)-carbamicacid tert-butyl ester

Boc-tranexamic acid (0.14 g, 0.54 mmol), Bop reagent (0.24 g, 0.54 mmol)and TEA (0.38 mL, 2.7 mmol) were added together with 10 mL of THF. Themixture was stirred at rt for 15 minutes under N₂, and the product fromExample 120 Part E (0.26 g, 0.45 mmol) was added. The resulting mixturewas heated at 75° C. for 15 minutes under N₂. The reaction mixture wascooled to rt and the solvent was removed. The residue was dissolved inEtOAc and washed with water and brine. It was dried over MgSO₄,concentrated, and purified by flash chromatography (40 g silica, 10-100%EtOAc in hexane) to give 0.21 g of the desired product. MS: 580.3,(M+H)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 0.94 (m, 2H), 1.25-1.37 (m, 4H),1.42 (s, 9H), 1.76-1.79 (m, 3H), 2.15 (m, 1H), 2.85 (m, 2H), 3.20-3.30(m, 2H), 5.17 (m, 1H), 7.16-7.23 (m, 5H), 7.67-7.80 (m, 3H).

Part G: trans-4-Aminomethyl-cyclohexanecarboxylic acid{(S)-1-[5-chloro-4-(4-cyano-3-fluoro-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-amide

The product from Example 120 Part F (0.21 g, 0.36 mmol) was stirred withCH₂Cl₂ (8 mL) and TFA (2 mL) under N₂ for 0.5 h. The solvents wereremoved. The residue was dried under vacuum to give 0.25 g of thebis-TFA salt. MS: 480.3, (M+H)⁺.

Part H: trans-4-Aminomethyl-cyclohexanecarboxylic acid{(S)-1-[4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenyl-ethyl}-amide,bis-trifluoroacetic acid salt

The product from Example 120 Part G (0.21 g, 0.36 mmol) and hydrazinemonohydrate (0.69 mL) were added together with 8 mL of n-butanol. Themixture was heated at 120° C. under N₂ for 1 h. The solvent was removed.The residue was purified by reverse phase HPLC to give 0.14 g of thetitle compound as the bis-TFA salt. MS: 492.3, (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 0.82-0.84 (m, 2H), 1.11-1.22 (m, 2H), 1.36 (m, 1H), 1.52 (m,1H), 1.61-1.70 (m, 3H), 2.02 (m, 1H), 2.52-2.61 (m, 2H), 2.94-3.09 (m,2H), 5.15 (m, 1H), 7.13-7.20 (m, 5H), 7.77-8.27 (m, 3H).

Example 121N—((S)-1-(4-(3-Amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-4-(aminomethyl)benzamide,bis-trifluoroacetic acid salt

Example 121 was prepared by the appropriate application of theprocedures described for Example 120, where4-((tert-butoxycarbamoyl)methyl)benzoic acid instead of Boc-tranexamicacid was used in Example 120 Part F. MS: 486.3, (M+H)⁺. ¹H NMR (500 MHz,d₄-MeOH) δ 3.33-3.35 (m, 2H), 4.18 (s, 2H), 5.44 (t, J=7.42 Hz, 1H),7.22-7.25 (m, 5H), 7.52-7.55 (m, 3H), 7.72 (s, 1H) 7.88 (d, J=8.25 Hz,2H), 7.97 (d, J=8.80 Hz, 1H).

Example 1223-Amino-N—((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-1H-indazole-6-carboxamide,bis-trifluoroacetic acid salt

Part A: tert-Butyl(S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethylcarbamate

The product from Part D of Example 120 (0.52 g, 1.2 mmol) was convertedto the aminoindazole by appropriate application of the method describedin Part H of Example 120. MS: 453.3 (M+H)⁺.

Part B:6-(2-((S)-1-Amino-2-phenylethyl)-5-chloro-1H-imidazol-4-yl)-1H-indazol-3-amine

The Boc protecting group in the product from Example 122 Part A wasremoved with TFA as described in Part G of Example 120. LC/MS: 353.1(M−H)⁺.

Part C:N—((S)-1-(4-(3-Amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-4-cyano-3-fluorobenzamide

The product from Example 122 Part B was coupled with4-cyano-3-fluorobenzoic acid using the methods described in Part F ofExample 120. MS: 500.3 (M+H)⁺.

Part D:3-Amino-N—((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-1H-indazole-6-carboxamide,bis-trifluoroacetic acid salt

The product from Example 122 Part C was converted to Example 122 usingthe method described in Part H of Example 120. MS: 510.3 (M−H)⁻. ¹H NMR(400 MHz, d₄-MeOH) δ 3.37 (m, 2H), 5.45 (t, J=7.42 Hz, 1H), 7.23-7.27(m, 5H), 7.54-7.58 (m, 2H), 7.72 (s, 1H), 7.86 (s, 1H), 7.91-7.97 (m,2H).

Example 1233-Amino-N—((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)benzo[d]isoxazole-6-carboxamide,bis-trifluoroacetic acid salt

The product from Part C of Example 122 was converted to theaminobenzisoxazole with acetohydroxamic acid and potassium carbonate inDMF. MS: 513.1 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 3.37 (m, 2H), 5.44(t, J=7.42 Hz, 1H), 7.23-7.27 (m, 5H), 7.54 (d, J=8.79 Hz, 1H), 7.68 (d,J=8.24 Hz, 1H), 7.72 (s, 1H), 7.82 (d, J=8.24 Hz, 1H), 7.83 (s, 1H),7.97 (d, J=8.79 Hz, 1H).

Example 124N—((S)-1-(4-(3-Amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-4-(aminomethyl)-2-fluorobenzamide,bis-trifluoroacetic acid salt

Example 124 was prepared by appropriate application of the proceduresdescribed for Example 120, where 4-cyano-2-fluorobenzoic acid instead ofBoc-tranexamic acid was used in Example 120 Part F. The cyano group wasreduced with (Boc)₂O/NiCl₂/NaBH₄ in MeOH at 0° C. The title compound wasisolated as the bis-TFA salt after TFA deprotection by appropriateapplication of the procedure described for Example 2 Part B. MS: 504.1,(M+H)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 3.34 (m, 2H), 4.18 (s, 2H), 5.44 (t,J=7.42 Hz, 1H), 7.20-7.27 (m, 5H), 7.33-7.35 (m, 2H), 7.54 (dd, J=8.34Hz and 1.31 Hz, 1H), 7.75 (m, 2H), 7.97 (d, J=9.22 Hz, 1H).

Example 128N—((S)-1-(4-(3-Amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-4-chloro-2-fluorobenzamide,bis-trifluoroacetic acid salt

Example 128 was prepared similarly by appropriate application of theprocedures for Example 120, where 4-chloro-2-fluorobenzoic acid insteadof Boc-tranexamic acid used in Example 120 Part F. MS: 509.3, (M+H)⁺. ¹HNMR (500 MHz, d₄-MeOH) δ 3.34 (m, 2H), 5.44 (t, J=7.42 Hz, 1H),7.21-7.34 (m, 7H), 7.53 (dd, J=8.79 Hz and 1.1 Hz, 1H), 7.66 (t, J=8.24Hz, 1H), 7.72 (s, 1H), 7.99 (d, J=8.79 Hz, 1H).

Example 129N—((S)-1-(4-(3-Amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-2-fluoro-5-methoxybenzamide,bis-trifluoroacetic acid salt

Example 121 was prepared similarly by appropriate application of theprocedures described for Example 120, where 2-fluoro-5-methoxybenzoicacid instead of Boc-tranexamic acid used in Example 120 Part F. MS:505.3, (M+H)⁺. ¹H NMR (500 MHz, d₄-MeOH) δ 3.34 (m, 2H), 3.78 (s, 3H),5.44 (t, J=7.42 Hz, 1H), 7.06 (m, 1H), 7.12 (m, 1H), 7.19 (m, 1H),7.23-7.27 (m, 5H), 7.55 (dd, J=8.79 Hz and 1.1 Hz, 1H), 7.73 (s, 1H),7.98 (d, J=8.79 Hz, 1H).

Example 130(S)-4-[2-[(1-[4-(Aminomethyl)cyclohexanecarboxamido]-2-phenylethyl]-4-chloro-1H-imidazol-5-yl]-benzamide,bis-trifluoroacetic acid salt

The product from Part A of Example 28 was chlorinated with NCS/CHCl₃ atRT using the procedure described in Example 120 Part D. The Boc groupwas then removed using the procedure for Example 2 Part B to give thefinal product as the bis-TFA salt. MS: 506.2 (M+1)⁺. ¹H NMR (400 MHz,d₄-MeOH) δ 1.05 (m, 2H), 1.38 (m, 2H), 1.56 (m, 1H), 1.75 (m, 1H), 1.85(d, J=10.55 Hz, 3H), 2.20 (m, 1H), 2.76 (d, J=7.03 Hz, 2H), 3.17 (m,2H), 5.20 (t, J=7.91 Hz, 1H), 7.21 (m, 5H), 7.73 (d, J=8.79 Hz, 2H),7.92 (d, J=8.79 Hz, 2H).

Example 131 trans-Cyclohexane-1,4-dicarboxylic acid 1-amide4-({(S)-1-[4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenyl-ethyl}-amide),bis-trifluoroacetic acid salt

Example 131 was prepared similarly by appropriate application of theprocedures for Example 120, where4-trans-(methoxycarbonyl)cyclohexanecarboxylic acid instead ofBoc-tranexamic acid was used in Example 120 Part F. The intermediatemethyl ester was then converted to the amide by sequential applicationof the procedures used for Example 26 Part A and Example 44 Part A. MS:506.2, (M+H)⁺. ¹H NMR (500 MHz, d₄-MeOH) δ 1.33-1.38 (m, 1H), 1.45-1.48(m, 3H), 1.72 (m, 1H) 1.88 (m, 3H), 2.18-2.23 (m, 2H), 3.17 (m, 1H),3.26 (m, 1H), 5.21 (t, J=7.42 Hz, 1H), 7.19 (m, 3H), 7.25 (m, 2H), 7.52(dd, J=8.24 Hz and 1.1 Hz, 1H), 7.70 (s, 1H), 7.99 (d, J=8.24 Hz, 1H).

Example 132(S)—N-[1-[4-(3-Amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl]-1,4-benzenedicarboxamide,bis-trifluoroacetic acid salt

Example 132 was prepared by appropriate application of the proceduresdescribed for Example 120 wherein 4-carbamoylbenzoic acid was usedinstead of Boc-tranexamic acid in Example 120 Part F. MS: 500.1, (M+H)⁺.¹H NMR (500 MHz, d₄-MeOH) δ 3.34 (m, 2H), 5.44 (t, J=7.42 Hz, 1H),7.24-7.26 (m, 5H), 7.54 (dd, J=8.79 and 1.1 Hz, 1H), 7.72 (s, 1H), 7.89(d, J=8.3 Hz, 2H), 7.95 (d, J=8.3 Hz, 2H), 7.97 (d, J=8.79 Hz, 1H).

Example 135(S)-4-[2-[1-[4-(Aminomethyl)cyclohexanecarboxamido]-2-phenylethyl]-4-phenyl-1H-imidazol-5-yl]-benzamide,bis-trifluoroacetic acid salt

The product from Part A of Example 28 was converted to(4-{(S)-1-[5-Bromo-4-(4-carbamoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethylcarbamoyl}-cyclohexylmethyl)-carbamicacid tert-butyl ester by appropriate application of the procedure forExample 82 Part A. This compound was then coupled with phenyl boronicacid by appropriate application of the conditions described for Example107 Part B. Deprotection of the Boc group with TFA using the procedurefrom Example 2 Part B afforded the Example 135 as the bis-TFA salt. MS:522.4 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ δ 1.07 (m, 2H), 1.42 (m, 2H),1.59 (m, 1H), 1.85 (m, 4H), 2.30 (m, 1H), 2.78 (d, J=6.59 Hz, 2H), 3.41(m, 2H), 5.32 (t, J=8.13 Hz, 1H), 7.29 (m, 7H), 7.44 (m, 2H), 7.90 (d,J=8.35 Hz, 2H).

Example 1361-Amino-N—((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-isoquinoline-6-carboxamide,bis-trifluoroacetic acid salt

This product was prepared using 1-aminoisoquinoline-6-carboxylic acidfrom Part D of Example 147 and the product from Part E of Example 120 bysequential application of the procedures described for Example 147 PartF and Example 120 Part F. MS: 523.2 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ3.39 (dd, J=15.82, 7.91 Hz, 2H), 5.48 (t, J=7.91 Hz, 1H), 7.25-7.27 (m,6H), 7.52 (d, J=10.11 Hz, 1H), 7.61 (d, J=7.03 Hz, 1H), 7.72 (s, 1H),7.96 (d, J=8.35 Hz, 1H), 8.08 (dd, J=8.79, 1.76 Hz, 1H), 8.30 (s, 1H),8.49 (d, J=8.79 Hz, 1H).

Example 1371-Amino-N—((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-5,6,7,8-tetrahydroisoquinoline-6-carboxamide,bis-trifluoroacetic acid salt

Example 137 was prepared from the product of Part F of Example 147 byappropriate application of the procedures for Example 120 Part H. MS:527.3 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 2.44 (m, 2H), 2.76 (m, 2H),2.88 (m, 1H), 3.21 (m, 2H), 3.34 (m, 2H) 5.29 (m, 1H), 6.66 (t, J=7.9Hz, 1H), 7.24 (m, 5H), 7.56 (m, 2H), 7.73 (s, 1H), 7.97 (d, J=7.9 Hz,1H).

Example 1382-(3-Amino-1H-indazol-6-yl)-N—((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)acetamide,bis-trifluoroacetic acid salt

This compound was prepared by appropriate application of the methodsdescribed for Example 122, wherein 2-(4-cyano-3-fluorophenyl)acetic acidws replaced by 4-cyano-3-fluorobenzoic acid. MS: 526.3 (M+1)⁺. ¹H NMR(400 MHz, d₄-MeOH) δ 3.17 (m, 1H), 3.26 (m, 1H), 3.69 (d, J=5.71 Hz,2H), 5.26 (t, J=7.03 Hz, 1H), 7.02 (d, J=8.34 Hz, 1H), 7.16 (m, 5H),7.26 (s, 1H), 7.52 (d, J=8.79 Hz, 1H), 7.71 (s, 1H), 7.81 (d, J=8.34 Hz,1H), 7.97 (d, J=8.79 Hz, 1H).

Example 139trans-4-(2-{(S)-1-[(4-Aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-5-bromo-1-methyl-1H-imidazol-4-yl)-benzamide,bis-trifluoroacetic acid salt

The product from Example 82 Part A was methylated with MeI/K₂CO₃/DMF.The major isomer isolated was deprotected using the procedure describedfor Example 2 Part B to give Example 139. MS: 538.2/540.2 (M+1)⁺. ¹H NMR(400 MHz, d₄-MeOH) δ 1.04 (m, 2H), 1.39 (m, 2H), 1.56 (m, 1H), 1.80 (m,4H), 2.20 (m, 1H), 2.76 (d, J=7.03 Hz, 2H), 3.27 (m, 2H), 3.41 (s, 3H),5.35 (t, J=7.91 Hz, 1H), 7.22 (m, 5H), 7.96 (m, 4H).

Example 1404-Aminomethyl-N-{(S)-1-[4-(4-carbamoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-2-ethylamino-benzamide,bis-trifluoroacetic acid salt

Part A: tert-Butyl 4-cyano-2-fluorobenzoate

4-Cyano-2-fluorobenzoic acid (1.0 g, 6.1 mmol) was dissolved in t-BuOH(9 mL) and THF (3 mL). Boc anhydride (2.64 g, 12.1 mmol) was addedfollowed by DMAP (0.24 g, 1.97 mmol). The mixture was stirred at RTunder N₂ for 12 h. The solvents were removed. The residue was dissolvedin EtOAc and washed with saturated aqueous NaHCO₃ and brine. It wasdried over MgSO₄ and concentrated to an oil which became solid undervacuum (1.3 g). ¹H NMR (400 MHz, d₄-MeOH) δ 1.59 (s, 9H), 7.44 (dd,J=25.71 and 9.01 Hz, 2H), 7.95 (m, 1H).

Part B: tert-Butyl 4-cyano-2-(ethylamino)benzoate

The product from Example 140 Part A (0.30 g, 1.36 mmol) and ethylaminehydrochloride (0.22 g, 2.72 mmol) were added together with 5 mL of DMF.The mixture was heated at 50° C. under N₂ for 2 h. Water was added, andthe mixture was extracted with EtOAc. The EtOAc extract was washed withbrine, dried over MgSO₄ and concentrated, and the residue was purifiedby flash chromatography (silica, EtOAc/hexane) to give 50 mg of thedesired product. MS: 247.3 (M+1)⁺.

Part C: 4-Cyano-2-(ethylamino)benzoic acid

The product from Example 140 Part B (50 mg, 0.20 mmol) was stirred with5 mL of TFA and 5 mL of CH₂Cl₂ at RT for 1 h, and then heated at refluxfor 1 h under N₂. The solvent was removed. The residue was dried to give45 mg of the acid. ¹H NMR (400 MHz, d₄-MeOH) δ 1.28 (m, 3H), 3.18 (m,2H), 76.75 (m, 1H), 6.86 (s, 1H), 7.95 (d, J=7.91 Hz, 1H).

Part D:(S)-4-(2-(1-(1-(4-Cyano-2-(ethylamino)phenyl)vinylamino)-2-phenylethyl)-1H-imidazol-4-yl)benzamide

Cyano-2-(ethylamino)benzoic acid from Example 140 Part C (40 mg, 0.2mmol), Bop reagent (108 mg, 0.24 mmol), and Et₃N (0.28 mL) were addedtogether with 5 mL of THF. The mixture was stirred at RT for 15 minutesand (S)-4-(2-(1-amino-2-phenylethyl)-1H-imidazol-4-yl)benzamide (107 mg,0.2 mmol), obtained from N-boc-(L)-phenylalanine and4-(2-bromo-acetyl)-benzonitrile by the sequential application of theprocedures described for Example 1 Part A, Example 28 Part A and Example1 Part B, was added. The resulting mixture was heated to reflux under N₂for 2 h. The solvent were removed. The residue was dissolved in EtOAcand washed with water and brine. It was dried over MgSO₄, concentrated,and purified by ISCO flash chromatography (silica, EtOAc/hexane) to give50 mg of the desired product. LC/MS: 479.3 (M+1)⁺.

Part E:4-Aminomethyl-N-{(S)-1-[4-(4-carbamoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-2-ethylamino-benzamide,bis-trifluoroacetic acid salt

The product from Example 140 Part D was dissolved in 10 mL of MeOH and 1mL of 4N HCl in dioxane. Catalytic amount of Pd/C (10%) was added. Themixture was placed under a balloon of H₂ for 12 h. It was filteredthrough CELITE®, concentrated, and purified by reverse phase HPLC togive 24 mg of bis-TFA salt. LC/MS: 483.4 (M+1)⁺. ¹H NMR (400 MHz,d₄-MeOH) δ 1.22 (t, J=7.25 Hz, 3H), 3.18 (q, J=7.03 Hz, 2H), 3.47 (dd,J=32.52 and 8.35 Hz, 2H), 4.05 (s, 2H), 5.50 (t, J=8.35 Hz, 1H), 6.66(d, J=7.91 Hz, 1H), 6.77 (s, 1H), 7.26 (m, 5H), 7.70 (d, J=7.91 Hz, 1H),7.76 (d, J=8.35 Hz, 2H), 7.88 (s, 1H), 7.98 (d, J=8.35 Hz, 2H).

Example 142(S)—N-(1-(4-(4-Carbamoylphenyl)-1H-imidazol-2-yl)-2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide

Example 142 was prepared by appropriate application of the methodsdescribed in Example 28. MS: 466.2 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ3.15 (t, J=6.37 Hz, 2H), 3.49 (m, 4H), 4.41 (s, 2H), 5.53 (t, J=8.35 Hz,1H), 7.27 (m, 6H), 7.75 (m, 4H), 7.88 (s, 1H), 7.97 (d, J=8.79 Hz, 2H).

Example 1434-Aminomethyl-N-{(S)-1-[4-(4-carbamoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-2-ethyl-benzamidePart A: Methyl 4-bromo-2-chlorobenzoate

2-Bromo-4-chlorobenzoic acid (1.0 g, 4.25 mmol) was dissolved in 10 mLof MeOH. The mixture was cooled in an ice-bath and to it was addedthionyl chloride (3.1 mL, 42.5 mmol) dropwise. The cooling bath wasremoved and the mixture was stirred at rt under N₂ for 12 h. The solventwas removed and dried under vacuum to give 1.0 g of colorless oil.LC/MS: 251.1 (M+1)⁺.

Part B: Methyl 2-chloro-4-cyanobenzoate

The product from Example 143 Part A (1.0 g, 4.0 mmol), Zn(CN)₂ (0.52 g,4.8 mmol), Pd(PPh₃)₄ (0.23 g, 0.2 mmol) were added together with 9 mL ofDMF. The mixture was degassed and then heated at 90° C. for 6 h. Waterand EtOAc were added to the reaction mixture. It was filtered to removeinorganic solids. The layers were separated and the EtOAc layer waswashed with water and brine. It was dried over MgSO₄, concentrated, andpurified by flash chromatography (silica, EtOAc/hexane) to give 0.28 gof the desired product. MS: 196.1 (M+1)⁺.

Part C: Methyl 4-cyano-2-ethylbenzoate

The product from Example 143 Part B (160 mg, 0.82 mmol), ethyl boronicacid (120 mg, 1.64 mmol), K₃PO₄ (344 mg (1.64 mmol), and Pd(PPh₃)₄ (114mg, 0.1 mmol) were added together with 9 mL of DME. The mixture washeated at 150° C. in a microwave for 15 minutes. The DME was removed andEtOAc was added. It was washed with water and brine, dried over MgSO₄,concentrated, and purified by flash chromatography (silica,EtOAc/hexane) to give 100 mg of the desired product. MS: 190.21 (M+H⁺)⁺and 222.3 (M+Na⁺)⁺.

Part D: 4-Cyano-2-ethylbenzoic acid

The product from Example 143 Part C (100 mg, 0.53 mmol) was dissolved in5 mL of EtOH and 1 mL of 1N aqueous NaOH was added. The mixture wasstirred at RT under N₂ for 2 h. Aqueous 1N HCl was added to adjust thepH to 4. The EtOH was removed, and the mixture was diluted with EtOACand water. The two layers were separated. The water layer was extractedwith EtOAc. The combined EtOAc solution was washed with water and brine,dried over MgSO₄, and concentrated to give 90 mg of the desired acid. ¹HNMR (400 MHz, d₄-MeOH) δ 1.22 (m, 3H), 3.00 (m, 2H), 7.71 (m, 1H), 7.67(s, 1H), 7.92 (d, J=8.35 Hz, 1H).

Part E:N-{(S)-1-[4-(4-Carbamoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-4-cyano-2-ethyl-benzamide

The product from Example 143 Part D (90 mg, 0.51 mmol), Bop reagent (265mg, 0.61 mmol), and triethylamine (0.42 mL, 1.5 mmol) were addedtogether with 5 mL of THF. The mixture was stirred at RT under N₂ for 15minutes and (S)-4-(2-(1-amino-2-phenylethyl)-1H-imidazol-4-yl)benzamideprepared using the methods described in Examples 2 and 28 (365 mg, 0.51mg) was added. The resulting mixture was heated at 75° C. for 70minutes. The THF was removed, and the residue was dissolved in EtOAc. Itwas washed with waster and brine, dried over MgSO₄, concentrated, andpurified by flash chromatography (silica, EtOAc/hexane) to give 80 mg ofthe desired product. MS: 464.4 (M+1)⁺.

Part F:4-Aminomethyl-N-{(S)-1-[4-(4-carbamoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-2-ethyl-benzamide

The product from Example 143 Part E (70 mg, 0.15 mmol) was dissolved in10 mL of MeOH and 1 mL of 4 N HCl in dioxane. Catalytic amount of Pd/C(10%) was added and the mixture was placed under a balloon of H₂ for 6h. It was filtered through CELITE® and washed with MeOH. The filtratewas concentrated and purified by reverse phase HPLC to give 75 mg of thebis-TFA salt. LC/MS: 468.4 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 1.08 (t,J=7.47 Hz, 3H), 2.61 (t, J=7.47 Hz, 2H), 3.44 (dd, J=13.62, 8.35 Hz,2H), 4.12 (s, 2H), 5.59 (t, J=8.35 Hz, 1H), 7.34 (m, 7H), 7.80 (d,J=8.35 Hz, 2H), 7.89 (s, 1H), 7.99 (d, J=8.35 Hz, 2H).

Example 1443-Amino-N—((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-1-methyl-1H-indazole-6-carboxamide,bis-trifluoroacetic acid salt

The product from Part C of Example 122 was converted to the desiredproduct by appropriate application of the method described in Part H ofExample 120, where methyl hydrazine was used instead of hydrazine. MS:526.3 (M+H)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 3.35 (m, 2H), 3.84 (s, 3H),5.46 (m, 1H), 7.23 (m, 5H), 7.39 (d, J=8.35 Hz, 2H), 7.64 (s, 1H), 7.72(d, J=8.35 Hz, 1H), 7.79 (s, 1H), 7.84 (d, J=7.91 Hz, 1H).

Example 1471-Amino-N—((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-5,6,7,8-tetrahydroisoquinoline-6-carboxamide,bis-trifluoroacetic acid salt

Part A: (E)-2-(2-(Dimethylamino)vinyl)terephthalonitrile

Methylterephthalonitrile (1.42 g, 1.0 mmol) andt-butoxybis(dimethylamine)methane (3.5 g, 2.0 mmol) were heated with 15mL of DML at 75° C. for 12 h under N₂. The DMF was removed and hexanewas added. The precipitate formed was filtered and dried to give 1.85 gof the desired product. MS: 504.4, (M+H)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ2.95 (s, 6H), 5.27 (d, J=13.62 Hz, 1H), 7.14 (m, 1H), 7.42 (d, J=13.18Hz, 1H), 7.54 (d, J=7.91 Hz, 1H), 7.86 (s, 1H).

Part B:2-(2,4-Dimethoxybenzyl)-1-imino-1,2-dihydroisoquinoline-6-carbonitrile

The product from Example 147 Part A (1.85 g, 9.38 mmol) and2,4-dimethoxybenzylamine (2.6 mL, 15.03 mmol) were heated with 5 mL ofDMPU at 140° C. for 3 h under N₂. The reaction mixture was cooled, andEtOAc/hexane (1:2) was added. The precipitate formed was filtered anddried in vacuo to give 2.5 g of the desired product. ¹H NMR (400 MHz,DMSO-d₆) δ 3.72 (s, 3H, 3.81 (s, 3H), 4.95 (s, 2H), 6.10 (d, J=7.03 Hz,1H, 6.44 (d, J=7.91 Hz, 1H), 6.57 (s, 1H), 7.02 (d, J=8.35 Hz, 1H), 7.22(d, J=6.15 Hz, 1H) 7.68 (d, J=7.91 Hz, 1H), 7.94 (s, 1H), 8.34 (d,J=7.91 Hz, 1H).

Part C:2-(2,4-Dimethoxybenzyl)-1-imino-1,2-dihydroisoquinoline-6-carboxylicacid

The product from Example 147 Part B (2.5 g, 7.84 mmol) was heated with40 mL of MeOH-15% NaOH (1:1) at 90° C. for 1.5 h under N₂. The reactionmixture was cooled and aq. HCl was added dropwise to adjust the pH toabout 5. The methanol was removed and EtOAc/hexane (1:2) were added. Theprecipitate formed was filtered and dried to give 2.42 g of the desiredproduct. LC/MS: 339.2, (M+H)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 2.00 (s, 2H),3.82 (d, J=9.67 Hz, 6H), 6.62 (m, 2H), 7.23 (d, J=7.91 Hz, 2H), 7.50 (d,J=7.03 Hz, 1H), 8.23 (s, 1H), 8.31 (s, 1H), 8.42 (d, J=8.79 Hz, 1H).

Part D: 1-Aminoisoquinoline-6-carboxylic acid

The product from Example 147 Part C (2.12 g, 6.28 mmol) was heated with17 mL of anisole and 20 mL of TFA at 105° C. for 12 h under N₂. Thesolvents were removed, and EtOAc/hexane (1:2) were added. Theprecipitate formed was filtered and dried to give 1.77 g of the TFAsalt. LC/MS: 189.04, (M+H)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 7.34 (d, J=7.03Hz, 1H), 7.62 (d, J=7.03 Hz, 1H), 8.30 (d, J=8.79 Hz, 1H), 8.51 (d,J=8.79 Hz, 1H), 8.56 (s, 1H).

Part E: 1-Amino-5,6,7,8-tetrahydroisoquinoline-6-carboxylic acid

The product from Example 147 Part D (1.0 g, 3.31 mmol) and platinumoxide (87 mg, 0.38 mmol) were added together with 21 mL of TFA. Thereaction mixture was placed under a balloon of hydrogen gas and thenwarmed to 60° C. for 16 h. The mixture was cooled to RT and filteredthrough CELITE® to remove platinum oxide. The solvent was removed, andthe residue was purified by reverse phase HPLC to give 0.21 g of thedesired product as the TFA salt. LC/MS: 193.1, (M+H)⁺. ¹H NMR (400 MHz,d₄-MeOH) δ 2.00 (m, 1H), 2.28 (m, 1H), 2.57 (m, 2H) 2.85 (m, 1H), 3.02(d, J=7.03 Hz, 2H), 6.75 (d, J=6.59 Hz, 1H), 7.61 (d, J=6.59 Hz, 1H).

Part F:1-Amino-N—((S)-1-(4-chloro-5-(4-cyano-3-fluorophenyl)-1H-imidazol-2-yl)-2-phenylethyl)-5,6,7,8-tetrahydroisoquinoline-6-carboxamide

The product from Example 147 Part E (0.21 g, 0.67 mmol), Bop reagent(0.44 g, 1.0 mmol), and triethylamine (0.91 mL, 6.54 mmol) were addedtogether with 15 mL of THF. The mixture was stirred at RT for 20 minutesunder N₂ and the product from Part E of Example 120 (0.41 g, 0.90 mmol)was added. The resulting mixture was heated at 75° C. for 1 h under N₂.The reaction mixture was cooled and the solvent was removed. The residuewas dissolved in EtOAc and washed with water and brine. It was driedover MgSO₄, concentrated, and purified by flash chromatography (40 gsilica, 0-15% MeOH in dichloromethane) to give 0.31 g of the desiredproduct. LC/MS: 515.4, (M+H)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 1.73 (dd,J=12.96, 5.93 Hz, 1H), 2.10 (m, 1H) 2.39 (m, 1H), 2.58 (m, 4H), 3.22 (m,2H), 5.24 (t, J=7.69 Hz, 1H), 6.37 (d, J=5.27 Hz, 1H), 7.23 (m, 5H),7.64 (m, 3H) 7.79 (m, 1H).

Part G: Chiral separation of the product from Part F

The product from Example 147 Part F was separated by chiral prep-HPLC(OD column, 30% EtOH/MeOH (1:1) and 70% heptane with 0.15% DEA) to givediastereomer A and diastereomer B.

Part H: (S)-1-Amino-5,6,7,8-tetrahydro-isoquinoline-6-carboxylic acid{(S)-1-[4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenyl-ethyl}-amide

Diastereomer A from Example 147 Part G (0.10 g, 0.19 mmol) and hydrazine(0.50 mL) were added together with 7 mL of n-butanol. The mixture washeated at 120° C. under N₂ for 1.5 h. The solvent was removed. Theresidue was purified by reverse phase HPLC to give 0.10 g of the desiredproduct as the bis-TFA salt. LC/MS: 527.21, (M+H)⁺. ¹H NMR (400 MHz,d₄-MeOH) δ 1.84 (m, 1H), 2.14 (m, 1H), 2.51 (m, 2H), 2.72 (m, 3H), 3.19(m, 2H), 5.24 (m, 1H), 6.66 (d, J=6.59 Hz, 1H), 7.24 (m, 5H), 7.49 (d,J=8.35 Hz, 1H), 7.59 (d, J=6.59 Hz, 1H) 7.69 (s, 1H), 7.93 (d, J=9.23Hz, 1H).

Example 155N—((S)-1-(4-(3-Amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,bis-trifluoroacetic acid salt

Example 155 was prepared by appropriate application of the proceduresdescribed for Example 120, where2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acidinstead of Boc-tranexamic acid was used in Example 120 Part F. MS:512.2, (M+H)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 3.17 (t, J=6.37 Hz, 2H, 3.35(m, 2H) 3.53 (t, J=6.37 Hz, 2H), 4.41 (s, 2H), 5.41 (t, J=7.91 Hz, 1H),7.22 (m, 5H), 7.32 (d, J=8.35 Hz, 1H), 7.50 (d, J=10.11 Hz, 1H) 7.71 (m,3H) 7.94 (d, J=8.35 Hz, 1H).

Example 157 trans-4-Aminomethyl-cyclohexanecarboxylic acid{(S)-1-[5-(3-amino-1H-indazol-6-yl)-1H-imidazol-2-yl]-3-[(pyridin-2-ylmethyl)-carbamoyl]-propyl}-amide,tris-trifluoroacetic acid salt Part A:(S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester1-[2-(4-cyano-3-fluoro-phenyl)-2-oxo-ethyl]ester

(S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester (674mg, 2 mmol), Cs₂CO₃ (326 mg, 1 mmol) and DMF 5 mL) were stirred roomtemperature for 0.5 h. A solution ofl′-bromo-3-fluoro-4-cyanoacetophenone (484 mg, 2 mmol) in DMF (5 mL) wasadded. Stirring was continued for 16 h. The reaction mixture was dilutedwith EtOAc (100 mL). Three washings with a 10% LiC1 solution, dryingover MgSO₄, filtration and removal of solvent in vacuo provided anorange oil (900 mg, 91% yield): ¹H NMR (CDCl₃, 400 MHz): δ 7.77 (m, 3H),7.35 (m, 5H), 5.52 (m, 1H), 5.42 (d, 1H, J=16), 5.25 (d, 1H, J=16), 5.11(s, 2H), 4.60 (m, 1H), 2.45 (m, 2H), 1.44 (s, 9H); MS: 497 (M−H⁺)⁻.

Part B:(S)-4-Benzyloxycarbonylamino-4-[5-(4-cyano-3-fluoro-phenyl)-1H-imidazol-2-yl]-butyricacid tert-butyl ester

The intermediate from Example 157 Part A (900 mg, 1.81 mmol), NH₄OAc(1.54 g, 20 mmol) and xylenes (30 mL) were stirred at reflux temperaturefor 2.5 h. The reaction mixture was cooled to ambient temperature.Solvent was removed in vacuo. The residue was partitioned between EtOAcand a saturated Na₂CO₃ solution three times. The combined organic layerswere dried over MgSO₄ and filtered. Solvent was removed in vacuo to givea red orange oil. HPLC (0% to 100% EtOAc-hexanes) gave an orange oil(400 mg, 46% yield): ¹H NMR (CDCl₃, 400 MHz): δ 10.3 (s, 1H), 7.59 (m,4H), 7.35 (m, 5H), 5.83 (s, 1H), 5.13 (m, 2H), 4.79 (m, 1H), 2.53 (m,1H), 2.34 (m, 3H), 1.45 (s, 9H); MS: 477 (M−H⁺)⁻.

Part C:(S)-4-Amino-4-[5-(4-cyano-3-fluoro-phenyl)-1H-imidazol-2-yl]-butyricacid tert-butyl ester

The intermediate from Example 157 Part B (400 mg, 0.84 mmol), 10% Pd onC (40 mg) and EtOH (4 mL) were stirred under a hydrogen atmosphere for 2h. The reaction mixture was filtered through CELITE®. Solvent wasremoved in vacuo to give an oil. HPLC (0% to 10% MeOH—CH₂Cl₂) provided apale yellow solid (189 mg, 65% yield): ¹H NMR (CDCl₃, 400 MHz): δ 10.3(s, 1H), 7.59 (m, 2H), 7.34 (1, 2H), 4.81 (t, 1H, J=7), 2.59 (m, 2H),2.28 (m, 2H), 1.42 (s, 9H); MS: 343 (M−H⁺)⁻.

Part D:trans-(S)-4-{[4-(Benzyloxycarbonylamino-methyl)-cyclohexanecarbonyl]-amino}-4-[5-(4-cyano-3-fluoro-phenyl)-1H-imidazol-2-yl]-butyricacid tert-butyl ester

N-CBz-tranexamic acid (160 mg, 0.66 mmol), HOBt.H₂O (82 mg, 0.61 mmol),EDCI (117 mg, 0.61 mmol), (i-Pr)₂NEt (388 mg, 0.52 mL, 3 mmol) and DMF(1 mL) were stirred at room temperature for 15 min. A solution of theintermediate from Example 157 Part C (189 mg, 0.55 mmol) in DMF (1 mL)was added. Stirring was continued for 24 h. The reaction mixture wasdiluted with EtOAc (40 mL). The organic mix was washed with a 10% LiC1solution. Drying over MgSO₄, filtration and removal of solvent in vacuoafforded a tan solid (330 mg, 97% yield): ¹H NMR (CDCl₃, 400 MHz): δ10.1 (s, 1H), 7.60 (m, 1H), 7.35 (m, 2H), 6.97 (d, 1H, J=8), 5.09 (s,2H), 4.90 (d, 1H, J=8), 4.81 (m, 1H), 3.06 (t, 2H, J=7), 2.37 (m, 2H),2.27 (m, 1H), 1.87 (m, 2H), 1.46 (s, 9H), 1.03 (m, 2H); HRMS (ES⁺):Calcd for C₃₄H₄₁FN₅O₅: 618.3092. Found: 618.3098 (M+H⁺)⁺.

Part E:trans-(S)-4-{[4-(Benzyloxycarbonylamino-methyl)-cyclohexanecarbonyl]-amino}-4-[5-(4-cyano-3-fluoro-phenyl)-1H-imidazol-2-yl]-butyricacid

The intermediate from Example 157 Part D (330 mg, 0.53 mmol), TFA (0.5mL) and CH₂Cl₂ (0.5 mL) were stirred at ambient temperature for 2 h.Solvent was removed in vacuo to give a tan solid (300 mg, 100% yield):¹H NMR (DMSO-d₆, 400 MHz): δ 8.24 (m, 1H), 8.04 (s, 1H), 7.97 (m, 1H),7.88 (d, 1H, J=9), 7.81 (d, 1H, J=9), 7.35 (m, 6H), 7.25 (m, 1H), 5.01(s, 2H), 5.0 (m, 1H), 3.63 (m, 1H), 3.13 (m, 1H), 2.86 (m, 2H), 2.31 (m,2H), 2.15 (m, 2H), 2.04 (m 1H), 1.75 (m, 2H), 1.27 (m, 5H), 0.88 (m,1H); HRMS (ES⁺): Calcd for C₃₀H₃₃FN₅O₅: 562.2466. Found: 562.2453(M+H)⁺.

Part F:trans-(4-{(S)-1-[5-(4-Cyano-3-fluoro-phenyl)-1H-imidazol-2-yl]-3-[(pyridin-2-ylmethyl)-carbamoyl]-propylcarbamoyl}-cyclohexylmethyl)-carbamicacid benzyl ester

The intermediate from the Example 157 Part E (325 mg, 0.53 mmol),HOBt.H₂O (81 mg, 0.6 mmol), EDC (115 mg, 0.6 mmol), (i-Pr)₂NEt (388 mg,0.52 mL, 3.0 mmol) and DMF (1 mL) were stirred at room temperature undera nitrogen atmosphere for 15 min. 2-Aminomethylpyridine (65 mg, 0.6mmol) was added, and stirring was continued for 88 h. The reactionmixture was diluted with EtOAc (20 mL) and the organic mix was washedwith a 10% LiC1 solution (5 mL) three times. The organic layer was driedover MgSO₄ and filtered. Solvent was removed in vacuo. HPLC (0% to 10%MeOH—CH₂Cl₂) provided a pale yellow solid (40 mg, 12% yield): ¹H NMR(MeOH-d₄, 400 MHz): δ 8.49 (m, 1H), 7.81 (t, 1H, J=8), 7.73 (m, 2H),7.35 (m, 11H), 5.08 (s, 1H), 4.50 (s, 2H), 3.37 (m, 4H), 2.98 (d, 2H,J=7), 2.40 (m, 2H), 2.25 (m, 2H), 1.86 (m, 6H), 1.47 (m, 2H), 1.05 (m,2H); HRMS (ES⁺): Calcd for C₃₆H₃₉FN₇O₄: 652.3048. Found: 652.3063 (M+H).

Part G: trans-4-Aminomethyl-cyclohexanecarboxylic acid{(S)-1-[5-(4-cyano-3-fluoro-phenyl)-1H-imidazol-2-yl]-3-[(pyridin-2-ylmethyl)-carbamoyl]-propyl}-amide,tris-trifluoroacetic acid salt

The intermediate from Example 157 Part F (98 mg, 0.15 mmol) and asolution of HBr in acetic acid (33%, 3 mL) were stirred at ambienttemperature for 21 h. Solvent was removed in vacuo to provide an oil.Reverse phase HPLC (0% to 100% CH₃CN—H₂O with 0.1% TFA) provided a whitesolid (20 mg, 39% yield): ¹H NMR (MeOH-d₄, 400 MHz): δ 8.70 (d, 1H,J=5), 8.38 (t, 1H, J=8), 8.00 (s, 1H), 7.80 (m, 5H), 5.18 (t, 1H, J=6),4.93 (m, 5H), 4.69 (d, 1H, J=16), 4.63 (d, 1H, J=16), 2.78 (d, 2H, J=7),2.51 (m, 2H), 2.31 (m, 4H), 1.62 (m, 2H), 1.45 (m, 4H), 1.09 (m, 2H);HRMS (ES⁺): Calcd for C₂₈H₃₃FN₇O₂: 518.2680. Found: 518.2698 (M+H).

Part H: trans-4-Aminomethyl-cyclohexanecarboxylic acid{(S)-1-[5-(3-amino-1H-indazol-6-yl)-1H-imidazol-2-yl]-3-[(pyridin-2-ylmethyl)-carbamoyl]-propyl}-amide,tris-trifluoroacetic acid salt

The intermediate from Example 157 Part F (20 mg, 0.02 mmol), hydrazinehydrate (0.5 mL) and n-BuOH (0.5 mL) were heated in a microwaveapparatus for 15 min at 120° C. Solvent was removed in vacuo to providea white solid (10 mg, 49% yield): ¹H NMR (MeOH-d₄, 400 MHz): δ 8.48 (d,1H, J=2), 7.80 (t, 1H, J=8), 7.67 (m, 2H), 7.35 (m, 4H), 5.11 (t, 1H,J=7), 4.86 (m, 8H), 4.50 (s, 2H), 3.57 (t, 1H, J=7), 2.81 (d, 2H, J=7),2.39 (m, 2H), 2.24 (m, 4H), 1.95 (m, 4H), 1.53 (m, 2H), 0.96 (t, 2H,J=7); HRMS (ES⁺): Calcd for C₂₈H₃₆N₉O₂: 530.2992. Found: 530.2991 (M+H).

Example 158 trans-4-Aminomethyl-cyclohexanecarboxylic acid{(S)-1-[5-phenyl-1H-imidazol-2-yl]-3-[(pyridin-2-ylmethyl)-carbamoyl]-ethyl}-amide

This compound was prepared following the procedures described in Example157, Parts A through H: ¹H NMR (MeOH-d₄, 400 MHz): δ 8.30 (d, 1H, J=8),7.58 (d, 2H, J=8), 7.43 (t, 1H, J=8), 7.25 (m, 3H), 7.13 (m, 2H), 7.05(d, 1H, J=8), 5.40 (t, 1H, J=7), 4.76 (m, 5H), 4.38 (d, 1H, J=16), 4.30(d, 1H, J=16), 2.94 (dd, 1H, J=15.7), 2.84 (dd, 1H, J=15.7), 2.43 (d,2H, J=7), 2.10 (m, 1H), 1.77 (m, 4H), 1.34 (m, 4H), 0.89 (m, 1H); HRMS(ES⁺): Calcd for C₂₆H₃₃N₆O₂: 461.2665. Found: 461.2657 (M+H).

Example 159N-[2-(2S)-[2-[4-(3-Amino-1H-indazol-6-yl)-1H-imidazol-2-yl]-2-[[trans-[4-(aminomethyl)cyclohexanecarboxamido]ethyl]phenyl]-phenylacetamide,bis-trifluoroacetic acid salt Part A:trans-{4-[(S)-1-[4-(4-Cyano-3-fluoro-phenyl)-1H-imidazol-2-yl]-2-(2-nitro-phenyl)-ethylcarbamoyl]-cyclohexylmethyl}-carbamicacid tert-butyl ester

L-2-Nitro-N-(Boc)-phenylalanine (2.24 g, 7.23 mmol) was treatedsequentially according to the procedures described in Example 1 Part Aand Part B and Example 2 Part A to yield 3.0 g (98% yield) of thedesired product. MS 450 (M−H)⁻.

Part B:trans-(4-{(S)-2-(2-Amino-phenyl)-1-[4-(4-cyano-3-fluoro-phenyl)-1H-imidazol-2-yl]-ethylcarbamoyl}-cyclohexylmethyl)-carbamicacid tert-butyl ester

The product from Example 159 Part A (284 mg, 0.48 mmol) was dissolvedacetic acid (3.5 mL) and 5 drops of water. Iron powder (273 mg, 4.8mmol) was added to the flask, and the reaction was heated to 50° C. for5 h. The reactions was cooled to rt, diluted with 50 mL of MeOH, andfiltered through CELITE®. The solvents were removed in vacuo to yield265 mg (98% yield) of the crude aniline. MS 559 (M−H)⁻.

Part C:trans-{4-[(S)-1-[4-(4-Cyano-3-fluoro-phenyl)-1H-imidazol-2-yl]-2-(2-phenylacetylamino-phenyl)-ethylcarbamoyl]-cyclohexylmethyl}-carbamicacid tert-butyl ester

The product from Example 159 Part B (132 mg, 0.23 mmol) and phenylacetic acid (40 mg, 0.28 mmol) were dissolved in pyridine (0.7 mL, 0.71mmol) and 1.5 mL of DMF. HOBt (45 mg, 0.3 mmol) and EDCI (60 mg, 0.30mmol) were added to the flask, and the reaction was stirred at rt for 12h. The reaction was diluted with EtOAc, extracted with ½ sat. brine (4-6times), dried over MgSO₄, filtered and evaporated to dryness to yieldthe desired product 150 mg (95% yield). MS 677 (M−H)⁻.

Part E: trans-4-Aminomethyl-cyclohexanecarboxylic acid[(S)-1-[4-(4-cyano-3-fluoro-phenyl)-1H-imidazol-2-yl]-2-(2-phenylacetylamino-phenyl)-ethyl]-amide

The product from Example 159 Part C (150 mg, 0.22 mmol) was treatedunder the condition described in Example 2 Part B and purified by prepHPLC (MeOH/H₂O/0.1% TFA gradient) to yield 18 mg (14% yield) of thedesired product. MS 577 (M−H)⁻.

Part F: trans-4-Aminomethyl-cyclohexanecarboxylic acid[(S)-1-[4-(3-amino-1H-indazol-6-yl)-1H-imidazol-2-yl]-2-(2-phenylacetylamino-phenyl)-ethyl]-amide,bis trifluoroacetic acid salt

The product from Example 159 Part D (18 mg, 0.03 mol) was treated underthe conditions described in Example 120 Part H to yield 2.3 mg (11%yield) of Example 159. ¹H NMR (500 MHz, MeOH-d₄) δ 0.93-1.11 (m, 1H)1.35 (ddd, J=58.97, 12.78, 3.57 Hz, 1H) 1.48-1.62 (m, 1H) 1.59-1.73 (m,1H) 1.74-1.92 (m, 2H) 2.10-2.31 (m, 1H) 2.76 (d, J=7.15 Hz, 1H) 3.75 (q,J=13.75 Hz, 1H) 5.24 (t, J=8.25 Hz, 1H) 7.05-7.22 (m, 2H) 7.26-7.33 (m,1H) 7.37 (t, J=6.60 Hz, 2H) 7.63 (s, 1H) 7.78 (s, 1H) 7.88 (d, J=8.80Hz, 1H) HRMS m/z Calc'd for C₃₄H₃₉N₈O₂ (M+H)⁺: 591.3196 Found 591.3221.

Example 162(S)-4-(Aminomethyl)-N-[1-[4-(4-amino-7-quinazolinyl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl]-trans-cyclohexanecarboxamide,bis-trifluoroacetic acid salt

Part A:(4-{(S)-1-[4-(4-Amino-quinazolin-7-yl)-5-chloro-1H-imidazol-2-yl]-2-phenyl-ethylcarbamoyl}-cyclohexylmethyl)-carbamicacid tert-butyl ester

The product from Example 120 Part F (0.53 g, 0.9 mmol) and formamidineacetate (1.5 g, 14.4 mmol) were added together with 20 mL of DMAC. Themixture was heated at 140° C. under N₂ for 8 h. Additional formamidine(1.5 g, 14.4 mmol) was added, and the mixture was heated for additional12 h. The mixture was cooled and water was added. The mixture wasadjusted to pH 7 with aqueous NaHCO₃, and it was then extracted withEtOAc. The combined EtOAC extracts were washed with brine, dried overMgSO₄, concentrated, and purified by flash chromatography (120 g silica,0-10% MeOH in CH₂Cl₂) to give 80 mg of the desired product. LC/MS:604.1, 606.1, (M+H)⁺.

Part B: 4-Aminomethyl-cyclohexanecarboxylic acid{(S)-1-[4-(4-amino-quinazolin-7-yl)-5-chloro-1H-imidazol-2-yl]-2-phenyl-ethyl}-amide,bis-trifluoroacetic acid salt

The product from Example 162 Part A (80 mg, 0.13 mmol) was stirred withCH₂Cl₂ (5 mL) and TFA (2 mL) under N₂ for 0.5 h. The solvents wereremoved. The residue was purified by reverse phase HPLC to give 75 mg ofthe desired product as the bis-TFA salt. MS: 504.4, (M+H)⁺. ¹H NMR (400MHz, d₄-MeOH) δ 1.02-1.06 (m, 2H), 1.34-1.47 (m, 2H), 1.55 (bs, 1H),1.75-1.90 (m, 4H), 2.22 (m, 1H), 2.76 (d, J=7.03 Hz, 2H), 3.12-3.24 (m,2H), 5.20 (m, 1H), 7.16-7.22 (m, 5H), 8.00 (m, 1H), 8.13 (s, 1H), 8.34(m, 1H), 8.65 (s, 1H).

Example 175N-[1-[4-(3-Amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-[3-(difluoromethoxy)phenyl]ethyl]-4-(aminomethyl)-trans-cyclohexanecarboxamide,bis-trifluoroacetic acid salt Part A:2-(Benzhydrylidene-amino)-3-(3-difluoromethoxy-phenyl)-propionic acidethyl ester

N-(Diphenylmethylene)glycine ethyl ester (500 mg, 1.87 mmol),tetrabuylammonium bromide (63 mg, 0.187 mmol) and3-(difluoromethoxy)benzyl bromide (0.5 mL, 1.87 mmol) were placed in aflask. The flask was evacuated and backfilled with argon Anhyddchloromethane was added to the flask, and the reaction was cooled indry-ice acetone bath to −78° C.2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine(0.7 mL, 2.44 mmol) was added slowly under argon at −78° C. The reactionwas allowed to stir at −78° C. for 30 minutes, and then warmed to roomtemperature over 16 h. The solvent was removed under vacuum. The residuewas pre-adsorbed on to SiO₂ and the product was isolated via SiO₂ toyield 700 mg of light yellow oil. MS 424.0 (M+H)⁺.

Part B: 2-Amino-3-(3-difluoromethoxy-phenyl)-propionic acid ethyl ester

The product from Example 175 Part A (700 mg, 1.65 mmol) was placed in aflask and dissolved in THF (30 mL). 30% (w/v) Citric acid (aqueoussolution, 30 mL) was added and the reaction was stirred at rt for 72 h.The solution was extracted with diethyl ether (50 mL), and the aqueouslayer was adjusted to a pH 6 using a saturated NaHCO₃ solution. Theaqueous solution was extracted with dichloromethane, washed with brine,dried over MgSO₄, filtered and evaporated to yield 420 mg (97% yield) ofa clear glass. MS 260 (M+H)⁺.

Part C:trans-2-{[4-(tert-Butoxycarbonylamino-methyl)-cyclohexanecarbonyl]-amino}-3-(3-difluoromethoxy-phenyl)-propionicacid ethyl ester

The product from Example 175 Part B (420 mg, 1.62 mmol) was treatedusing the procedure described in Example 2 Part A to yield 800 mg (97%yields) of a white solid. MS 497 (M−H)⁻.

Part D:trans-2-{[4-(tert-Butoxycarbonylamino-methyl)-cyclohexanecarbonyl]-amino}-3-(3-difluoromethoxy-phenyl)-propionicacid

The product from Example 175 Part C (800 mg, 1.6 mmol) was treatedaccorded to the procedure described in Example 26 to yield 750 mg of awhite tacky solid. MS 469 (M−H)⁻.

Part E: trans-4-Aminomethyl-cyclohexanecarboxylic acid[1-[4-(3-amino-1H-indazol-6-yl)-1H-imidazol-2-yl]-2-(3-difluoromethoxy-phenyl)-ethyl]-amide,bis-trifluroracetic acid salt

The product from Example 175 Part D (284 mg, 0.6 mmol) was treatedsequentially according to the procedures described in Example 1 Part A,Example 2 Part B and Example 120 Part H to yield 1.1 mg (9% yield) ofthe title compound as a clear glass after purification by prep HPLC. ¹HNMR (500 MHz, MeOH-d₄) δ 0.98-1.20 (m, 1H) 1.33 (s, 1H) 1.49-1.65 (m,1H) 1.74-1.91 (m, J=11.55 Hz, 1H) 2.25 (s, 1H) 2.77 (d, J=7.15 Hz, 1H)3.16 (s, 1H) 3.55-3.69 (m, 1H) 5.34 (t, J=7.97 Hz, 1H) 6.77 (s, 1H) 7.00(s, 1H) 7.06 (dd, J=24.74, 8.25 Hz, 1H) 7.33 (t, J=7.97 Hz, 1H) 7.77 (d,J=8.25 Hz, 1H) 7.84 (s, 1H) 7.98 (d, J=8.80 Hz, 1H); HRMS m/z Calc'd forC₂₇H₃₂N₅O₃F₂ (M+H)⁺: 512.2473 Found 512.2485.

Example 176(S)-3-Amino-N-[1-[4-[4-(carbamimidoyll)phenyl]-1H-imidazol-2-yl]-2-phenylethyl]-1H-indazole-5-carboxamide

Part A: 4-[2-((S)-1-Amino-2-phenyl-ethyl)-1H-imidazol-4-yl]-benzonitriledihydrochloride salt

{(S)-1-[4-(4-Cyanophenyl)-1H-imidazol-2-yl]-2-phenylethyl} carbamic acidtert-butyl ester prepared as described in Ex. 28, Part A (1.0 g, 2.57mmol) was dissolved in dioxane (10 mL) and 4 N HCl in dioxane (10 mL)and an additional 5 mL dioxane were added. The resulting mixture wasstirred for 2-2.5 h at room temperature under N₂, then diluted withether. The resulting solid was triturated with additional ether andcollected by filtration, washed with ether and hexane and dried toprovide the amine dihydrochloride salt as a light green solid (0.89 g,96%). ¹H NMR (500 MHz, DMSO-d₆) δ 3.25-3.32 (m, 1H) 3.33-3.40 (m, 1H)4.60 (s, 1H) 7.11 (d, J=7.15 Hz, 2H) 7.16-7.29 (m, 3H) 7.78-7.89 (m, 3H)7.95 (d, J=8.25 Hz, 2H) 8.65 (s, 2H). m/z 289.2 (M+H)⁺.

Part B:3-Cyano-N-{(S)-1-[4-(4-cyano-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-4-fluorobenzamide

A mixture of the compound of Example 176 Part A (100 mg, 0.28 mmol),3-cyano-4-fluorobenzoic acid (46 mg, 0.28 mmol), triethylamine (0.085mL, 0.61 mmol) and BOP (0.18 g, 0.4 mmol) in THF (5 mL) was stirred atrt overnight under N₂. Reaction mixture was diluted with water andextracted 3× with EtOAc. The combined extracts were washed with sat'd.NaHCO₃ and brine and then dried over anhydrous Na₂SO₄, filtered andevaporated. Chromatography on silica gel (hexane/EtOAc) provided theamide product (88 mg, 72%). ¹H NMR (500 MHz, CDCl₃) δ 3.41 (dd, J=13.75,7.15 Hz, 1H) 3.58 (dd, J=13.47, 7.97 Hz, 1H) 5.33 (q, J=7.70 Hz, 1H)7.01-7.09 (m, 1H) 7.18-7.37 (m, 7H) 7.66 (d, J=8.25 Hz, 2H) 7.85 (d,J=8.25 Hz, 2H) 7.89-7.96 (m, 1H) 7.95-8.03 (m, 1H) 9.74 (s, 1H). m/z436.1 (M+H)⁺.

Part C: 3-Amino-1H-indazole-6-carboxylic acid{(S)-1-[4-(4-cyano-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-amide

The compound of Example 176 Part B (86 mg, 0.20 mmol) was dissolved innBuOH (2 mL) and excess hydrazine (0.1 mL) was added. The mixture washeated in a sealed tube at 160° C. for 10 min using microwaveirradiation. Reaction mixture was cooled to room temperature, dilutedwith water and extracted with EtOAc (2×). The combined extracts werewashed with water and brine, dried over Na₂SO₄, filtered and evaporated.The crude aminoindazole [m/z 448.1 (M+H)⁺] was used without purificationin the next step.

Part D: N-3-Amino-1H-indazole-5-carboxylic acid{(S)-1-[4-(4-carbamimidoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-amide

The compound of Example 176 Part C was dissolved in ethanol (8 mL) andthe solution stirred in an ice bath while HCl(g) was bubbled through thesolution for 10-15 min. The flask was then tightly capped and kept inthe refrigerator overnight. Flask was warmed to room temperature, andcontents stirred for 3-4 h, then ethanol was evaporated. The resultingresidue was triturated with ether to give a solid which was collected byfiltration and dried in vacuo. The imidate thus obtained was redissolvedin ethanol (5 mL) and excess ammonium carbonate (0.2 g) added. Themixture was stirred in a tightly capped flask for 48 h at roomtemperature. The reaction mixture was diluted with methanol, decantedand evaporated to dryness. The residue was redissolved in methanol andpurified by prep C18 HPLC to provide the bis TFA salt of the titleamidine product as an off-white solid (85 mg, 61%) after evaporation ofsolvents. ¹H NMR (500 MHz, DMSO-d₆) δ 3.35-3.47 (m, 2H) 5.51 (q, J=7.15Hz, 1H) 7.18 (t, J=7.15 Hz, 1H) 7.21-7.34 (m, 6H) 7.80 (d, J=8.80 Hz,1H) 7.89 (d, J=8.25 Hz, 2H) 7.99 (d, J=8.80 Hz, 2H) 8.03-8.15 (m, 1H)8.32 (s, 1H) 8.94 (s, 1H) 9.03 (s, 2H) 9.31 (s, 2H) 11.86 (s, 1H). m/z465.0 (M+H)⁺.

Example 182 N—{(S)-1-[4-(4-Carbamimidoyl-phenyl)-1-ethyl-1H-imidazol-2-yl]-2-phenyl-ethyl}-benzamide

Part A:N-{(S)-1-[4-(4-Cyano-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-benzamide

The compound of Example 176 Part A (0.15 g, 0.42 mmol) was coupled withbenzoic acid using the procedure of Example 176 Part B to provide thetitle compound (0.12 g, 76%). ¹H NMR (400 MHz, CDCl₃) δ 3.45-3.65 (m,2H) 5.34 (d, J=8.35 Hz, 1H) 6.82 (d, J=7.47 Hz, 1H) 7.19-7.35 (m, 7H)7.40 (t, J=7.69 Hz, 2H) 7.45-7.56 (m, 1H) 7.64 (d, J=7.03 Hz, 4H) 7.86(d, J=8.35 Hz, 2H). m/z 393.1 (M+H)⁺.

Part B:N-{(S)-1-[4-(4-Cyano-phenyl)-1-ethyl-1H-imidazol-2-yl]-2-phenyl-ethyl}-benzamide

The compound of Example 182 Part A (60 mg, 0.15 mmol) was dissolved inDMF (2.5 mL) and potassium carbonate (32 mg, 0.23 mmol) was addedfollowed by ethyl iodide (0.015 mL, 0.19 mmol), and the resultingmixture was stirred overnight at room temperature. The reaction mixturewas diluted with water and extracted with EtOAc (3×). The combinedextracts were washed with water and brine, then dried over Na₂SO₄,filtered and evaporated. The residue was chromatographed on silica gelto provide the product (48 mg, 76%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.17(t, J=7.25 Hz, 3H) 3.34-3.48 (m, 2H) 3.89-4.05 (m, 2H) 5.46 (d, J=7.03Hz, 1H) 7.14 (d, J=7.03 Hz, 1H) 7.21 (t, J=7.47 Hz, 2H) 7.31 (d, J=7.47Hz, 2H) 7.41 (t, J=7.25 Hz, 2H) 7.48 (d, J=7.03 Hz, 1H) 7.76-7.84 (m,3H) 7.88 (s, 1H) 7.94 (d, J=8.79 Hz, 2H) 9.08 (d, J=8.35 Hz, 1H). m/z421.2 (M+H)⁺.

Part C:N-{(S)-1-[4-(4-Carbamimidoyl-phenyl)-1-ethyl-1H-imidazol-2-yl]-2-phenyl-ethyl}-benzamide

The compound of Example 182 Part B (17 mg) was dissolved in ethanol (2mL) and hydroxylamine hydrochloride (15 mg, 5 eq) and triethylamine(0.03 mL, 5 eq) were added. The mixture was heated in a sealed tube at125° C. for 15 min using microwave irradiation. Additional aliquots ofhydroxylamine hydrochloride and triethylamine were added and microwaveirradiation repeated for an additional 10 min at 120° C. Solvent wasevaporated, and the residue redissolved in acetic acid (2 mL) andtreated with acetic anhydride (0.015 mL, 3 eq). The solution was stirredfor 15 min at room temperature followed by addition of zinc dust (25 mg,10 eq) and a little MeOH. Mixture was then stirred overnight at roomtemperature. The reaction was filtered through a pad of CELITE® andsolids washed with MeOH. Filtrate was evaporated, and residue purifiedby prep C18 HPLC to provide the bis-TFA salt of the title compound as awhite solid (16 mg, 60%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.20 (t, J=7.03Hz, 3H) 3.33-3.52 (m, 2H) 3.93-4.10 (m, 2H) 5.49 (d, J=7.47 Hz, 1H) 7.16(t, J=7.47 Hz, 1H) 7.23 (t, J=7.25 Hz, 2H) 7.32 (d, J=7.03 Hz, 2H) 7.43(t, J=7.47 Hz, 2H) 7.51 (t, J=7.47 Hz, 1H) 7.84 (dd, J=7.69, 5.49 Hz,4H) 7.95 (s, 1H) 8.00 (d, J=8.35 Hz, 2H) 8.92 (s, 2H) 9.12 (d, J=7.91Hz, 1H) 9.25 (s, 2H). m/z 450.2 (M+H)⁺.

Example 183N1-{(S)-1-[4-(4-Carbamimidoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-2-fluoro-terephthalamidePart A:((S)-1-{4-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1H-imidazol-2-yl}-2-phenyl-ethyl)-carbamicacid tert-butyl ester

{(S)-1-[4-(4-Cyanophenyl)-1H-imidazol-2-yl]-2-phenylethyl} carbamic acidtert-butyl ester prepared as described in Example 28 Part A (1.00 equiv;2.57 mmoles; 1.00 g) was dissolved in 15 mL EtOH and hydroxylaminehydrochloride (12.87 mmoles; 894.42 mg) and triethylamine (12.87 mmoles;1.79 mL) were added. The resulting solution was heated at reflux in an80° C. oil bath under N₂ overnight. Reaction was cooled to roomtemperature and evaporated to remove EtOH. Residue was suspended in amixture of EtOAc/EtOH (˜10:1) and filtered to remove inorganic solids.Filtrate was reconcentrated to a yellow foam. This residue wasredissolved in 10 mL HOAc and treated with stirring under N₂ with aceticanhydride (4.23 mmoles; 400 μL). solution was stirred for 20 min at roomtemperature, then heated in 80° C. oil bath for 2 h, cooled to roomtemperature and stirred overnight. Most of HOAc was removed on rotaryevaporator, then residue was diluted with water and carefullyneutralized by addition of sat'd NaHCO₃ to pH˜8. Extracted 3× withCH₂Cl₂. Combined extracts were washed with brine then dried over MgSO₄,filtered and evaporated to a lt red foam. Residue was purified on silicagel to provide the product as a lt pinkish tan foam. (590 mg; 51.4%). ¹HNMR (500 MHz, CDCl₃) δ 1.41 (s, 9H) 2.65 (s, 3H) 3.28-3.44 (m, 2H) 4.88(d, J=7.70 Hz, 1H) 5.23 (s, 1H) 7.13-7.36 (m, 5H) 7.42-7.55 (m, 1H) 7.88(d, J=8.25 Hz, 2H) 8.06 (d, J=8.25 Hz, 2H) 9.67 (s, 1H). m/z 446.1(M+H)⁺.

Part B:(S)-1-{4-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1H-imidazol-2-yl}-2-phenyl-ethylaminedihydrochloride

The BOC group was removed from the compound of Example 183 Part A usingprocedure of Ex. 176, Part A to provide the hydrochloride salt of theamine as a tan solid in 46% yield. ¹H NMR (500 MHz, CDCl₃) δ 2.67 (s,3H) 2.87 (dd, J=13.75, 9.35 Hz, 1H) 3.44 (dd, J=13.75, 4.40 Hz, 1H) 4.44(dd, J=9.35, 4.40 Hz, 1H) 7.20-7.31 (m, 5H) 7.34 (t, J=7.42 Hz, 3H) 7.85(s, 1H) 8.08 (d, J=8.80 Hz, 2H). m/z 346.0 (M+H)⁺, 330.0 (M+H−NH₃)⁺.

Part C:4-Cyano-2-fluoro-N—((S)-1-{4-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1H-imidazol-2-yl}-2-phenyl-ethyl)-benzamide

The compound of Example 183 Part B was coupled to4-cyano-2-fluorobenzoic acid using the procedure of Example 176 Part Bto provide the amide in 90% yield. ¹H NMR (500 MHz, CDCl₃) δ ppm 2.64(s, 3H) 3.43 (dd, J=13.75, 7.15 Hz, 1H) 3.58 (dd, J=13.75, 7.70 Hz, 1H)5.38 (q, J=7.15 Hz, 1H) 7.20-7.33 (m, 7H) 7.42 (d, J=9.90 Hz, 1H) 7.54(d, J=8.25 Hz, 2H) 7.86 (s, 1H) 8.05 (d, J=8.25 Hz, 2H) 8.14 (t, J=7.70Hz, 1H) 9.43 (s, 1H). m/z 493.1 (M+H)⁺.

Part D:2-Fluoro-N1-((S)-1-{4-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1H-imidazol-2-yl}-2-phenyl-ethyl)-terephthalamide

A mixture of the compound of Example 183 Part C (75 mg, 0.15 mmol),potassium carbonate (66 mg, 3 eq) and 30% hydrogen peroxide (0.055 mL,11 eq) in DMSO (2.5 mL) was stirred at room temperature under N₂overnight. Reaction mixture was diluted with water and EtOAc, and phasesseparated. Aqueous phase was reextracted with EtOAc (2×). Combinedorganic phases were washed with water and brine, dried over anhydrousNa₂SO₄, filtered and evaporated. The resulting crude amide was usedwithout purification. m/z 511.0 (M+H)⁺.

Part E:N1-{(S)-1-[4-(4-Carbamimidoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-2-fluoroterephthalamide

The compound of Example 183 Part D (68 mg) and 10% Pd/C (35 mg, wet,Degussa) were suspended in a mixture of methanol and triethylamine (4.5ml, 8:1) and stirred under 1 atm H₂ overnight. Catalyst was removed byfiltration through CELITE® and washed with MeOH. Filtrate was evaporatedand residue purified by prep C18 HPLC to provide the bis TFA salt of thetitle compound as a white solid (48 mg, 53%). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 3.23-3.31 (m, 1H) 3.41 (dd, J=13.75, 6.60 Hz, 1H) 5.43 (q, J=7.70Hz, 1H) 7.13-7.23 (m, 1H) 7.23-7.31 (m, 5H) 7.59-7.66 (m, 2H) 7.67-7.77(m, 2H) 7.87 (t, J=7.70 Hz, 2H) 7.99 (d, J=8.25 Hz, 3H) 8.13 (s, 1H)8.95 (s, 2H) 8.98-9.06 (m, 1H) 9.27 (s, 2H). m/z 471.0 (M+H)⁺.

Example 188N1-((S)-1-(4-(3-Amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-2-fluoroterephthalamide,bis-trifluoroacetic acid salt

Example 188 was prepared similarly by appropriate application of theprocedures described for Example 120, where 4-carbamoyl-2-fluorobenzoicacid instead of Boc-tranexamic acid was used in Example 120 Part F. ¹HNMR (500 MHz, DMSO-d₆) δ 3.16 (dd, J=13.75, 8.80 Hz, 1H), 3.30 (dd,J=13.75, 6.05 Hz, 1H) 5.31-5.43 (m, 1H), 7.16-7.23 (m, 1H), 7.25-7.31(m, 5H), 7.38 (d, J=8.80 Hz, 1H), 7.55 (t, J=7.42 Hz, 1H), 7.62 (d,J=5.50 Hz, 2H), 7.65-7.76 (m, 2H), 7.86 (d, J=8.80 Hz, 1H), 8.12 (s,1H), 8.97 (d, J=8.25 Hz, 2H), 12.05 (s, 1H), 12.81 (s, 1H).

Example 189N1-((S)-1-(4-(4-Aminoquinazolin-7-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-2-fluoroterephthalamide,bis-trifluoroacetic acid salt

Example 189 was prepared by appropriate application of the proceduresfor Example 162, excluding Example 162 Part G and using4-carbamoyl-2-fluorobenzoic acid instead of Boc-tranexamic acid in theprocedure from Example 120 Part F. MS: 530.01, (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 3.14-3.24 (m, 1H), 3.25-3.35 (m, 1H) 5.31-5.44 (m, 1H),7.15-7.24 (m, 1H), 7.24-7.33 (m, 5H), 7.54 (t, J=7.70 Hz, 1H), 7.64 (s,1H), 7.66-7.76 (m, 3H), 7.99 (d, J=8.80 Hz, 1H), 8.13 (s, 2H), 8.46 (d,J=8.80 Hz, 1H), 8.80 (s, 1H), 9.07 (d, J=6.60 Hz, 1H), 13.20 (s, 1H).

Example 1901-Amino-N—((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-5,6,7,8-tetrahydroisoquinoline-6-carboxamide,bis-trifluoroacetic acid salt

Example 190 was similarly prepared by appropriate application of theprocedures for Example 147 Part H using the diastereomer B from Part Gof Example 147. ¹H NMR (400 MHz, d₄-MeOH) δ 1.75 (dd, J=13.40, 10.33 Hz,1H), 2.01 (m, 1H), 2.45 (t, J=6.37 Hz, 2H), 2.73 (m, 1H), 2.90 (m, 2H),3.20 (m, 2H), 5.28 (m, 1H), 6.69 (d, J=6.59 Hz, 1H), 7.25 (m, 5H), 7.51(d, J=8.79 Hz, 1H), 7.59 (d, J=6.59 Hz, 1H), 7.71 (s, 1H), 7.95 (d,J=8.79 Hz, 1H).

Example 1911-Amino-N—((S)-1-(4-(4-aminoquinazolin-7-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-5,6,7,8-tetrahydroisoquinoline-6-carboxamide,bis-trifluoroacetic acid salt

Example 191 was prepared using the product from Part F of Example 147 byappropriate application of the procedures described in Part A of Example162. LC/MS: 539.2 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 1.77 (m, 1H), 2.00(d, J=3.95 Hz, 1H) 2.45 (m, 2H), 2.74 (m, 2H) 2.91 (m, 1H), 3.21 (m,2H), 5.26 (m, 1H), 6.67 (t, J=7.25 Hz, 1H), 7.23 (m, 5H), 7.59 (t,J=6.59 Hz, 1H), 8.02 (m, 1H), 8.16 (d, J=4.39 Hz, 1H), 8.36 (dd, J=8.79and 1.76 Hz, 1H), 8.65 (s, 1H).

Example 1921-Amino-N—((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-3-methylisoquinoline-6-carboxamide,bis-trifluoroacetic acid salt

Part A: (Z)-3-(3-Bromophenyl)-2-methylacrylic acid

3-Bromobenziladelhyde (2.6 g, 0.014 mol) and(carbethoxyethylidene)triphenylphosphorane (5.6 g, 0.015 mol) were addedtogether with 30 mL of toluene. The mixture was stirred at RT under N₂for 24 h. The solvent was removed. The residue was dissolved in EtOAcand washed with water and brine. It was dried over MgSO₄, concentrated,and purified by flash chromatography (silica, Hexane/EtOAc) to give 3.7g of the desired ester. MS: 271.2/273.2 (M+1)⁺. The ester was thendissolved in 30 mL of THF and 10 mL of water. LiOH (1.32 g, 0.031 mol)was added. The mixture was stirred at RT under N₂ for 72 h. The THF wasremoved. The resulting mixture was diluted with water and extracted withEtOAc (discarded). The aqueous mixture was acidified with HCl andextracted with EtOAc. This EtOAc extract was washed with brine, driedover MgSO₄ and concentrated to a white solid (3.2 g). ¹H NMR (400 MHz,CDCl₃) δ 2.12 (s, 3H), 7.29 (m, 2H), 7.47 (d, J=7.91 Hz, 1H), 7.56 (s,1H), 7.73 (s, 1H).

Part B: 6-Bromo-3-methylisoquinolin-1(2H)-one

The product from Example 192 Part A (2.76 g, 11.45 mmol) andtriethylamine (3.60 mL, 22.90 mmol) were added together with 18 mL ofacetone. The mixture was cooled to 0° C., followed by the dropwiseaddition of ethyl chloroformate (1.85 mL, 17.17 mmol). The reactionmixture was stirred at 0-5° C. under N₂ for 1 h. To it was added theslurry of sodium azide (1.34 g, 20.60 mmol) in 2 mL of water. Thereaction mixture was stirred at rt under N₂ overnight. The solvent wasremoved. The residue was dissolved in EtOAc and washed with water andbrine. It was dried over MgSO₄, concentrated, and dried in vacuo to give3.4 g of 80% pure desired acyl azide. A solution of tributylamine (4.40mL, 18.49 mmol) and diphenylmethane (15 mL) was heated to 190° C. To itwas added dropwise the solution of the acyl azide (3.4 g of 80% purematerial, 10.3 mmol) in diphenylmethane (12 mL) over 12 minutes. Themixture was stirred at 220° C. for 2 h under N₂. It was cooled to RT.The crude product was precipitated and filtered. It was purified byflash chromatography (120 g silica, 0-10% MeOH in dichloromethane) togive 0.43 g of the desired product. MS: 238.2, 240.1 (M+1)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 2.20 (s, 3H), 6.30 (s, 1H), 7.52 (d, J=8.79 Hz, 1H),7.80 (s, 1H), 7.81 (d, J=8.35 Hz, 1H).

Part C: 6-Bromo-3-methylisoquinolin-1-amine

Phosphorus oxychloride (2.5 mL) was cooled in an ice-bath and was thenadded dropwise to the product from Example 192 Part B (120 mg, 0.5mmol). The mixture was heated to 110° C. under N₂ for 1.5 h. Thereaction was cooled, and quenched with water and MeOH. More water wasthen added. The solid was filtered and washed with 1N NaOH and water togive 115 mg of solid. The solid obtained (51 mg) was combined with 1 mLof 13-15% NH₃ in ethylene glycol. The mixture was heated in a sealedtube via microwave irradiation at 170° C. for 20 minutes. The reactionwas cooled and water was added. The solid was filtered and purified byISCO flash chromatography (silica, CH₂Cl₂/MeOH) to give 12 mg of thedesired product. MS: 237.1/239.1 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ2.39 (s, 3H), 6.76 (s, 1H), 7.53 (m, 1H), 7.81 (d, J=1.76 Hz, 1H), 7.98(d, J=8.79 Hz, 1H).

Part D: 1-Amino-3-methylisoquinoline-6-carbonitrile

The product from Example 192 Part C (22 mg, 0.093 mmol), Zn(CN)₂ (12mg), and Pd(PPh₃)₄ (8 mg) were added with 2 mL of DMF. The mixture washeated in a sealed tube in a microwave at 180° C. for 10 minutes. Themixture was filtered and washed with EtOAc. The filtrate wasconcentrated, and purified by flash chromatography (silica, CH₂Cl₂/MeOH)to give 12 mg of the desired product. LC/MS: 184.18 (M+1)⁺.

Part E: 1-Amino-3-methylisoquinoline-6-carboxylic acid

The product from Example 192 Part D (35 mg) was added with 4 mL of MeOHand 4 mL of 15% aqueous NaOH. The mixture was heated at 70-85° C. for 2h. It was concentrated, acidified with HCl and TFA to pH=5. The solidwas filtered and purified by reverse phase prep-HPLC to give 18 mg ofthe TFA salt. LC/MS: 203.03 (M+1)⁺.

Part F:1-Amino-N—((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-3-methylisoquinoline-6-carboxamide,bis-trifluoroacetic acid salt

The product from Example 192 Part E and the product from Part E ofExample 120 were coupled and then converted to the aminoindazole usingthe methods described in Example 120 Part F and Part H, respectively.MS: 537.0 (M+1)⁺. ¹H NMR (400 MHz, d₄-MeOH) δ 2.52 (s, 3H), 3.41 (m,2H), 5.46 (t, J=7.91 Hz, 1H), 7.05 (s, 1H), 7.23 (m, 5H), 7.50 (d,J=8.79 Hz, 1H) 7.71 (s, 1H), 7.98 (m, 2H), 8.19 (s, 1H), 8.43 (d, J=8.79Hz, 1H).

Example 200 4-Aminomethyl-cyclohexanecarboxylic acid{(S)-2-[4-(3-amino-1H-indazol-6-yl)-1H-imidazol-2-yl]-1-benzyl-ethyl}-amide,bis-trifluoroacetic acid salt

This compound was prepared following the procedures described in Example120: ¹H NMR (500 MHz, Solvent) δ 0.90-1.01 (m, 2H), 1.18-1.24 (m, 2H),1.42-1.50 (m, 1H), 1.50-1.62 (m, 2H), 1.68-1.79 (m, 2H), 2.00-2.09 (m,1H), 2.71 (d, J=7.15 Hz, 2H), 2.94 (dd, J=13.00, 8.80 Hz, 2H), 3.02 (dd,J=13.00, 6.04 Hz, 2H), 3.13 (dd, J=15.12, 10.17 Hz, 1H), 4.57-4.65 (m,1H), 7.18-7.23 (m, 1H), 7.26-7.30 (m, 4H), 7.47 (d, J=9.90 Hz, 1H), 7.74(s, 1H) 7.89 (s, 1H), 7.97 (d, J=8.25 Hz, 1H). HRMS (ES⁺): Calcd forC₂₇H₃₃N₇O: 471.2747. Found: 472.2839 (M+H).

Tables 1 to 6 below summarize the prepared examples of compounds in thepresent invention.

TABLE 1

Ex. No. A

R¹¹ Mass spec (m/z) (M + H)⁺ 1

410.20 14

417.27 15

483.07, 481.07 25

489.29 26

461.26 27

460.27 75

403.2 76

403.1 82

526.1, 524.1 83

410.2 84

453.2 86

489.2 106

589.5 107

514.2 108

410.2 112

397.4 113

538.4 114

504.4 115

530.2 116

512.3 117

440.2 118

458.2 119

491.2 120

492.4 121

486.3 122

510.3 (M − H⁺)⁻ 123

513.1 124

504.1 128

509.3 129

505.3 130

480.4 131

506.2 132

500.1 133

530.3 134

512.1 135

522.4 136

523.2 137

527.3 140

483.4 141

550.3 142

466.2 143

468.4 144

526.3 145

446.3 146

550.2 147

527.3 155

512.2 157

530.3 158

461.3 160

620.3 161

620.3 162

504.2 165

564.0 171

510.3 172

510.3 173

504.1 174

442.2 175

558.2 176

465.0 177

490.0 178

465.0 179

450.0 180

508.0 181

449.0 183

471.1 187

489.0 188

518.2 189

530.0 190

527.2 191

539.2 192

537.0 194

531.06 195

557.32 196

579.33 197

579.31 198

579.35 199

510.3 203

453.0 213

471.03 214

530.17 215

530.17 217

545.3 218

559.32 219

545.4 220

613.3 221

609.32 222

593.35 223

627.25 224

623.38 225

607.39 226

593.33 227

607.38 228

579.3 229

579.36 230

583.31 231

615.36 232

633.45 233

605.38 235

648.8 238

524.1 239

519.19 241

646.36 242

512.20 243

512.20 244

512.01 248

542.2 249

498.3 250

526.2 251

417.4 252

460.3 253

521.2 254

616.2 255

511.2 256

472.4 257

460.4 261

516.2 262

516.2 263

515.2 264

515.3 265

497.1 266

525.2 267

433.3 268

451.3 269

467.2 270

466.3 271

606.1 272

579.2 273

497.2 274

497.2 275

471.3 276

457.3 277

487.3 278

537.2 279

545.3 280

543.3 281

529.3 282

565.4 283

579.4 284

593.4 285

613.4 286

627.4 287

627.4 288

627.4 289

661.4 290

661.4 291

661.4 292

661.4 293

661.4 294

510.3 295

493.4 296

543.4 297

474.3 298

433.3 299

642.5 300

625.4 301

625.4 302

641.4 303

653.5 304

457.3 305

545.3 306

510.3 307

474.4 308

487.2 309

534.3 310

558.3 311

552.3 312

472.3 313

490.3 314

649.2 315

613.3 316

649.2 317

500.3 318

485.3 319

489.3

TABLE 2

Ex. No. A

R¹¹ Mass spec (m/z) (M + H)⁺  48

404.3  49

404.2  50

403.1  51

420.1  52

403.3 125

514.3 126

424.2 127

500.2 139

538.2 540.2 182

450.2

TABLE 3

Mass spec (m/z), Ex. No. R¹¹ R³ (M + H)⁺ 2

403.2 3

428.15 4

481.09 5

433.25 6

483.23 7

461.25 8 Me

327.21 9

417.27 10

471.24 11

471.24 12

421.24 13

428.30 16

437.21 17

437.21 18

404.25 19

404.25 20

433.26 21

432.18 22

404.25 23

404.25 24

404.25 28

446.26 29

446.2 30

460.27 31

474.29 32

443.25 33

444.24 34

460.22 35

457.27 36

468.21 37

—CO₂Me 385.33 38

—CO₂H 371.21 39

—CONHCH₂CO₂Et 478.24 40

—CONHCH₂CO₂H 428.22 41

—CONHBn 460.27 62

433.22 63

439.23 64

421.24 65

446.23 66

447.24 67

461.26 68

447.24 69

458.27 79

410.2 80

460.1 81

404.0 87

461.1 88

460.2 89

482.1 90

419.2 91

489.2 94

421.3 95

448.2 96

471.3 97

479.3 98

509.3 99

433.3 100

507.5 101

471.4 102

448.2 103

437.4 104

453.5 105

453.4 109

472.3 110

409.4 111

481.3 148

503.2 149

503.1 150

491.0 151

473.3 152

473.2 153

534.3 154

534.3 156

613.1 159

591.3 163

605.3 164

613.2 166

577.3 167

537.9 168

438.1 169

488.1 170

504.1 201

457.9 202

459.2 207

479.3 208

454.3 209

479.3 210

447.3 211

453.2 212

453.3 216

418.3 234

446.3 236

509.3 237

489.3 240

481.2 245

454.3 246

454.3 247

454.3 258

437.3 259

500.3 260

470.3

TABLE 4

Mass spec (m/z) Ex. No. R^(3a) (M + H)⁺ 42 CO₂Et 435.3 43 CO₂H 421.2 44CONH₂ 420.2 45 —CH₂CO₂Et 463.4 46 —CH₂CO₂H 435.4 47 —CH₂CONH₂ 434.3

TABLE 5

Ex. No. A L

R¹¹ Mass spec (m/z) (M + H)⁺ 53

—NHCO—

410.20 54

—NHCO—

410.20 55

—NHCO—

410.20 56

—NHCO—

453.20 57

—NHCO—

477.3 58

—NHCO—

462.19 59

—NHCO—

453.4 61

—NHCOCH₂—

424.21 77

NHCONH

418.1

TABLE 6

Mass spec (m/z) Ex. No. R¹⁰ (M + H)⁺ 70 Bn 493.20 71 —CH₂CH₂Ph 507.31 72—CH₂CH₂CO₂Et 489.62 74 —CH₂CH₂CONH₂ 474.62 85

578.4

Using combinations of the above described synthetic routes andexperimental procedures along with methods known to one skilled in theart of organic synthesis, additional compounds of this invention asshown below in Table 6 can be prepared.

TABLE 7

Ex. No. A

R¹¹ 1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1016

1017

1018

1019

1020

1021

1022

1024

1025

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070

1071

1072

1073

1074

1075

1076

1077

UTILITY

The compounds of this invention are inhibitors of factor XIa and areuseful as anticoagulants for the treatment or prevention ofthromboembolic disorders in mammals (i.e., factor XIa-associateddisorders). In general, a thromboembolic disorder is a circulatorydisease caused by blood clots (i.e., diseases involving fibrinformation, platelet activation, and/or platelet aggregation). The term“thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebovascular thromboembolic disorders, and thromboembolic disorders inthe chambers of the heart. The term “thromboembolic disorders” as usedherein also includes specific disorders selected from, but not limitedto, unstable angina or other acute coronary syndromes, atrialfibrillation, first or recurrent myocardial infarction, ischemic suddendeath, transient ischemic attack, stroke, atherosclerosis, peripheralocclusive arterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from (a) prosthetic valvesor other implants, (b) indwelling catheters, (c) stents, (d)cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures inwhich blood is exposed to an artificial surface that promotesthrombosis. It is noted that thrombosis includes occlusion (e.g., aftera bypass) and reocclusion (e.g., during or after percutaneoustransluminal coronary angioplasty). The thromboembolic disorders mayresult from conditions including but not limited to atherosclerosis,surgery or surgical complications, prolonged immobilization, arterialfibrillation, congenital thrombophilia, cancer, diabetes, effects ofmedications or hormones, and complications of pregnancy. Theanticoagulant effect of compounds of the present invention is believedto be due to inhibition of serine proteases involved in the coagulationcascade and/or contact activation system, more specifically, inhibitionof the coagulation factors: factor XIa, factor VIIa, factor IXa, factorXa, plasma kallikrein or thrombin.

The compounds of this invention also are inhibitors of plasma kallikreinand are useful as anti-inflammatory agents for the treatment orprevention of diseases associated with an activation of the contactactivation system (i.e., plasma kallikrein associated disorders). Ingeneral, a contact activation system disorder is a disease caused byactivation of blood on artificial surfaces, including prosthetic valvesor other implants, indwelling catheters, stents, cardiopulmonary bypass,hemodialysis, microorganism (e.g., bacteria, virus), or other proceduresin which blood is exposed to an artificial surface that promotes contactactivation, blood clots (i.e., diseases involving fibrin formation,platelet activation, and/or platelet aggregation). It also includessystemic inflammatory response syndrome, sepsis, acute respiratorydistress syndrome, hereditary angioedema or other inherited or acquireddeficiencies of contact activation components or their inhibitors(plasma kallikrein, factor XIIa, high molecular weight kininogen,Cl-esterase inhibitor). It may also include acute and chronicinflammations of joints, vessels, or other mammalian organs.

The effectiveness of compounds of the present invention as inhibitors ofthe coagulation factors XIa, VIIa, IXa, Xa, plasma kallikrein orthrombin, can be determined using a relevant purified serine protease,respectively, and an appropriate synthetic substrate. The rate ofhydrolysis of the chromogenic or fluorogenic substrate by the relevantserine protease was measured both in the absence and presence ofcompounds of the present invention. Hydrolysis of the substrate resultedin the release of pNA (para nitroaniline), which was monitoredspectrophotometrically by measuring the increase in absorbance at 405nm, or the release of AMC (amino methylcoumarin, which was monitoredspectrofluorometrically by measuring the increase in emission at 460 nmwith excitation at 380 nm. A decrease in the rate of absorbance orfluorescence change in the presence of inhibitor is indicative of enzymeinhibition. Such methods are known to one skilled in the art. Theresults of this assay are expressed as the inhibitory constant, K_(i).

Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethyleneglycol; JT Baker or Fisher Scientific). Determinations were made usingpurified human Factor XIa at a final concentration of 75-200 pM(Haematologic Technologies) and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; Chromogenix) at a concentration of 0.0002-0.00025M. In general, preferred compounds of the present invention, such as theparticular compounds disclosed in the above examples, have beenidentified to be active and exhibit K_(i)'s of equal to or less than 15μM in the Factor XIa assay, thereby demonstrating the utility of thecompounds of the present invention as especially effective inhibitors ofcoagulation Factor XIa. More preferred compounds have K_(i)'s of equalto or less than 5 μM, preferably equal to or less than 1 μM, morepreferably equal to or less than 0.5 μM.

Factor VIIa determinations were made in 0.005 M calcium chloride, 0.15 Msodium chloride, 0.05 M HEPES buffer containing 0.5% PEG 8000 at a pH of7.4. Determinations were made using purified human Factor VIIa(Haematologic Technologies) or recombinant human Factor VIIa (NovoNordisk) at a final assay concentration of 2-5 nM, recombinant solubletissue factor at a concentration of 18-35 nM and the synthetic substrateH-D-Ile-Pro-Arg-pNA (S-2288; Chromogenix or BMPM-2; AnaSpec) at aconcentration of 0.001 M. In general, compounds tested in the FactorVIIa assay are considered to be active if they exhibit a K_(i) of equalto or less than 15 μM.

Factor IXa determinations were made in 0.005 M calcium chloride, 0.1 Msodium chloride, 0.05 M TRIS base and 0.5% PEG 8000 at a pH of 7.4.Determinations were made using purified human Factor IXa (HaematologicTechnologies) at a final assay concentration of 20-100 nM and thesynthetic substrate PCIXA2100-B (CenterChem) or Pefafluor IXa 3688(H-D-Leu-Ph′Gly-Arg-AMC; CenterChem) at a concentration of 0.0004-0.0005M. In general, compounds tested in the Factor IXa assay are consideredto be active if they exhibit a K_(i) of equal to or less than 15 μM.

Factor Xa determinations were made in 0.1 M sodium phosphate buffer at apH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human Factor Xa (HaematologicTechnologies) at a final assay concentration of 150-1000 pM and thesynthetic substrate S-2222 (Bz-Ile-Glu (gamma-OMe, 50%)-Gly-Arg-pNA;Chromogenix) at a concentration of 0.0002-0.0003 M. In general,compounds tested in the Factor Xa assay are considered to be active ifthey exhibit a K_(i) of equal to or less than 15 μM.

Plasma kallikrein determinations were made in 0.1 M sodium phosphatebuffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG8000. Determinations were made using purified human kallikrein (EnzymeResearch Laboratories) at a final assay concentration of 200 pM and thesynthetic substrate S-2302 (H-(D)-Pro-Phe-Arg-pNA; Chromogenix) at aconcentration of 0.00008-0.0004 M. The Km value used for calculation ofKi was 0.00005 to 0.00007 M. In general, Compounds tested in the plasmakallikrein assay are considered to be active if they exhibit a K_(i) ofequal to or less than 15 μM.

Thrombin determinations were made in 0.1 M sodium phosphate buffer at apH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human alpha thrombin(Haematologic Technologies or Enzyme Research Laboratories) at a finalassay concentration of 200-250 pM and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; Chromogenix) at a concentration of 0.0002 M. Ingeneral, compounds tested in the thrombin assay are considered to beactive if they exhibit a K_(i) of equal to or less than 15 μM.

In general, preferred compounds of the present invention havedemonstrated K_(i) values of equal to or less than 15 μM in at least oneof the above assays, thereby confirming the utility of the compounds ofthe present invention as effective inhibitors of the coagulation cascadeand/or contact activation system, and useful as anticoagulants for theprevention or treatment of thromboembolic disorders in mammals and/or asanti-inflammatory agents for the prevention or treatment of inflammatorydisorders in mammals.

The Michaelis constant, K_(m), for substrate hydrolysis by each proteasewas determined at 25° C. using the method of Lineweaver and Burk. Valuesof K_(i) were determined by allowing the protease to react with thesubstrate in the presence of the inhibitor. Reactions were allowed to gofor periods of 20-180 minutes (depending on the protease) and thevelocities (rate of absorbance or fluorescence change versus time) weremeasured. The following relationships were used to calculate K_(i)values:(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m))) for a competitiveinhibitor with one binding site; orv _(s) /v _(o) =A+((B−A)/1+((IC ₅₀/(I)^(n)))); andK _(i) =IC ₅₀/(1+S/K _(m)) for a competitive inhibitor;where:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

A is the minimum activity remaining (usually locked at zero);

B is the maximum activity remaining (usually locked at 1.0);

-   -   n is the Hill coefficient, a measure of the number and        cooperativity of potential inhibitor binding sites;

IC₅₀ is the concentration of inhibitor that produces 50% inhibitionunder the assay conditions;

K_(i) is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate; and

K_(m) is the Michaelis constant for the substrate.

The effectiveness of compounds of the present invention as inhibitors ofthe coagulation factors XIa, VIIa, IXa, Xa, or thrombin, can bedetermined using relevant in vivo thrombosis models, including In VivoElectrically-induced Carotid Artery Thrombosis Models and In Vivo RabbitArterio-venous Shunt Thrombosis Models.

In Vivo Electrically-Induced Carotid Artery Thrombosis Model

The antithrombotic effect of compounds of the present invention can bedemonstrated in the electrically-induced carotid artery thrombosis(ECAT) model in rabbits. In this model, rabbits are anesthetized with amixture of ketamine (50 mg/kg i.m.) and xylazine (10 mg/kg i.m.). Afemoral vein and a femoral artery are isolated and catheterized. Thecarotid artery is also isolated such that its blood flow can be measuredwith a calibrated flow probe that is linked to a flowmeter. A stainlesssteel bipolar hook electrode is placed on the carotid artery andpositioned caudally in relationship to the flow probe as a means ofapplying electrical stimulus. In order to protect the surroundingtissue, a piece of Parafilm is placed under the electrode.

Test compounds are considered to be effective as anticoagulants based ontheir ability to maintain blood flow in the carotid artery following theinduction of thrombosis by an electrical stimulus. A test compound orvehicle is given as continuous intravenous infusion via the femoralvein, starting 1 hour before electrical stimulation and continuing tothe end of the test. Thrombosis is induced by applying a directelectrical current of 4 mA for 3 min to the external arterial surface,using a constant current unit and a d.c. stimulator. The carotid bloodflow is monitored and the time to occlusion (decrease of blood flow tozero following induction of thrombosis) in minutes is noted. The changein observed blood flow is calculated as a percentage of the blood flowprior to induction of thrombosis and provides a measure of the effect ofa test compound when compared to the case where no compound isadministered. This information is used to estimate the ED₅₀ value, thedose that increases blood flow to 50% of the control (blood flow priorto induction of thrombosis) and is accomplished by nonlinear leastsquare regression.

In Vivo Rabbit Arterio-Venous Shunt Thrombosis Model

The antithrombotic effect of compounds of the present invention can bedemonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. Inthis model, rabbits weighing 2-3 kg anesthetized with a mixture ofxylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. Asaline-filled AV shunt device is connected between the femoral arterialand the femoral venous cannulae. The AV shunt device consists of a pieceof 6-cm tygon tubing that contains a piece of silk thread. Blood willflow from the femoral artery via the AV-shunt into the femoral vein. Theexposure of flowing blood to a silk thread will induce the formation ofa significant thrombus. After forty minutes, the shunt is disconnectedand the silk thread covered with thrombus is weighed. Test agents orvehicle will be given (i.v., i.p., s.c., or orally) prior to the openingof the AV shunt. The percentage inhibition of thrombus formation isdetermined for each treatment group. The ID₅₀ values (dose whichproduces 50% inhibition of thrombus formation) are estimated by linearregression.

The anti-inflammatory effect of these compounds can be demonstrated inan Evans Blue dye extravasation assay using Cl-esterase inhibitordeficient mice. In this model, mice are dosed with a compound of thepresent invention, Evans Blue is injected via the tail vein, andextravasation of the blue dye is determined by spectrophotometric meansfrom tissue extracts.

The ability of the compounds of the current invention to reduce orprevent the systemic inflammatory response syndrome, for example, asobserved during on-pump cardiovascular procedures, can be tested in invitro perfusion systems, or by on-pump surgical procedures in largermammals, including dogs and baboons. Read-outs to assess the benefit ofthe compounds of the present invention include for example reducedplatelet loss, reduced platelet/white blood cell complexes, reducedneutrophil elastase levels in plasma, reduced activation of complementfactors, and reduced activation and/or consumption of contact activationproteins (plasma kallikrein, factor XII, factor XI, high molecularweight kininogen, Cl-esterase inhibitors).

The utility of the compounds of the current invention to reduce orprevent the morbidity and/or mortality of sepsis can be assessed byinjecting a mammalian host with bacteria or viruses or extracts there ofand compounds of the present invention. Typical read-outs of theefficacy include changes in the LD50 and blood pressure preservation.

The compounds of the present invention may also be useful as inhibitorsof additional serine proteases, notably human thrombin, human plasmakallikrein and human plasmin. Because of their inhibitory action, thesecompounds are indicated for use in the prevention or treatment ofphysiological reactions, including blood coagulation, fibrinolysis,blood pressure regulation and inflammation, and wound healing catalyzedby the aforesaid class of enzymes. Specifically, the compounds haveutility as drugs for the treatment of diseases arising from elevatedthrombin activity of the aforementioned serine proteases, such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. Theseinclude other anti-coagulant or coagulation inhibitory agents,anti-platelet or platelet inhibitory agents, anti-inflammatory agents,thrombin inhibitors, or thrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of the present invention that, when administeredalone or in combination with an additional therapeutic agent to amammal, is effective to treat (i.e., prevent, inhibit or ameliorate) thethromboembolic and/or inflammatory disease condition or treat theprogression of the disease in a host.

The compounds of the invention are preferably administered alone to amammal in a therapeutically effective amount. However, the compounds ofthe invention can also be administered in combination with an additionaltherapeutic agent, as define below, to a mammal in a therapeuticallyeffective amount. When administered in a combination, the combination ofcompounds is preferably, but not necessarily, a synergistic combination.Synergy, as described for example by Chou et al., Adv. Enzyme Regul.,22:27-55 (1984), occurs when the effect (in this case, inhibition of thedesired target) of the compounds when administered in combination isgreater than the additive effect of the compounds when administeredalone as a single agent. In general, a synergistic effect is mostclearly demonstrated at suboptimal concentrations of the compounds.Synergy can be in terms of lower cytotoxicity, increased anticoagulanteffect, or some other beneficial effect of the combination compared withthe individual components.

By “administered in combination” or “combination therapy” it is meantthat the compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

Compounds which can be administered in combination with the compounds ofthe present invention include, but are not limited to, anticoagulants,anti-thrombin agents, anti-platelet agents, fibrinolytics, hypolipidemicagents, antihypertensive agents, and anti-ischemic agents.

Other anticoagulant agents (or coagulation inhibitory agents) that maybe used in combination with the compounds of this invention includewarfarin, heparin (either unfractionated heparin or any commerciallyavailable low molecular weight heparin, for example LOVENOX®),aprotinin, synthetic pentasaccharide, direct acting thrombin inhibitorsincluding hirudin and argatroban, as well as other factor VIIa, VIIIa,IXa, Xa, XIa, thrombin, TAFI, and fibrinogen inhibitors known in theart.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function, for example, byinhibiting the aggregation, adhesion or granular secretion of platelets.Such agents include, but are not limited to, the various knownnon-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam,diclofenac, sulfinpyrazone, and piroxicam, including pharmaceuticallyacceptable salts or prodrugs thereof. Of the NSAIDS, aspirin(acetylsalicylic acid or ASA), and piroxicam are preferred. Othersuitable platelet inhibitory agents include IIb/IIIa antagonists (e.g.,tirofiban, eptifibatide, and abciximab), thromboxane-A2-receptorantagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors,phosphodiesterase-III (PDE-III) inhibitors (e.g., dipyridamole,cilostazol), and PDE V inhibitors (such as sildenafil), andpharmaceutically acceptable salts or prodrugs thereof.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, is also intended to include ADP (adenosine diphosphate) receptorantagonists, preferably antagonists of the purinergic receptors P₂Y₁ andP₂Y₁₂, with P₂Y₁₂ being even more preferred. Preferred P₂Y₁₂ receptorantagonists include ticlopidine and clopidogrel, includingpharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is aneven more preferred agent. Ticlopidine and clopidogrel are alsopreferred compounds since they are known to be gentle on thegastro-intestinal tract in use. The compounds of the present inventionmay also be dosed in combination with aprotinin.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the granular secretion of plasminogen activator inhibitor-1and/or serotonin), endothelial cell activation, inflammatory reactions,and/or fibrin formation are disrupted. A number of thrombin inhibitorsare known to one of skill in the art and these inhibitors arecontemplated to be used in combination with the present compounds. Suchinhibitors include, but are not limited to, boroarginine derivatives,boropeptides, heparins, hirudin and argatroban, includingpharmaceutically acceptable salts and prodrugs thereof. Boroargininederivatives and boropeptides include N-acetyl and peptide derivatives ofboronic acid, such as C-terminal alpha-aminoboronic acid derivatives oflysine, ornithine, arginine, homoarginine and correspondingisothiouronium analogs thereof. The term hirudin, as used herein,includes suitable derivatives or analogs of hirudin, referred to hereinas hirulogs, such as disulfatohirudin.

The term thrombolytic (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator (TPA,natural or recombinant) and modified forms thereof, anistreplase,urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factorVIIa inhibitors, PAI-I inhibitors (i.e., inactivators of tissueplasminogen activator inhibitors), alpha-2-antiplasmin inhibitors, andanisoylated plasminogen streptokinase activator complex, includingpharmaceutically acceptable salts or prodrugs thereof. The termanistreplase, as used herein, refers to anisoylated plasminogenstreptokinase activator complex, as described, for example, in EuropeanPatent Application No. 028,489, the disclosure of which is herebyincorporated herein by reference herein. The term urokinase, as usedherein, is intended to denote both dual and single chain urokinase, thelatter also being referred to herein as prourokinase.

Examples of suitable anti-arrythmic agents for use in combination withthe present compounds include: Class I agents (such as propafenone);Class II agents (such as carvadiol and propranolol); Class III agents(such as sotalol, dofetilide, amiodarone, azimilide and ibutilide);Class IV agents (such as ditiazem and verapamil); K⁺ channel openerssuch as I_(Ach) inhibitors, and I_(Kur) inhibitors (e.g., compounds suchas those disclosed in WO 01/40231).

The term antihypertensive agents, as used herein, include: alphaadrenergic blockers; beta adrenergic blockers; calcium channel blockers(e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil);diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,triamtrenene, amiloride, spironolactone); renin inhibitors;angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril,lisinopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, lisinopril); angiotensin-II receptorantagonists (e.g., irbestatin, losartan, valsartan); ET receptorantagonists (e.g., sitaxsentan, atrsentan and compounds disclosed inU.S. Pat. Nos. 5,612,359 and 6,043,265); Dual ET/AII antagonist (e.g.,compounds disclosed in WO 00/01389); neutral endopeptidase (NEP)inhibitors; vasopepsidase inhibitors (dual ACE/NEP inhibitors, e.g.,omapatrilat, gemopatrilat, nitrates); and β-blockers (e.g., propanolol,nadolo, or carvedilol).

Examples of suitable cardiac glycosides for use in combination with thecompounds of the present invention include digitalis and ouabain.

Examples of suitable mineralocorticoid receptor antagonists for use incombination with the compounds of the present invention includesprionolactone and eplirinone.

Examples of suitable cholesterol/lipid lowering agents and lipid profiletherapies for use in combination with the compounds of the presentinvention include: HMG-CoA reductase inhibitors (e.g., pravastatin,lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a.itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a.rosuvastatin, or atavastatin or visastatin)); squalene synthetaseinhibitors; fibrates; bile acid sequestrants (such as questran); ACATinhibitors; MTP inhibitors; lipooxygenase inhibitors; choesterolabsorption inhibitors; and cholesterol ester transfer protein inhibitors(e.g., CP-529414).

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include: biguanides (e.g.,metformin); glucosidase inhibitors (e.g., acarbose); insulins (includinginsulin secretagogues or insulin sensitizers); meglitinides (e.g.,repaglinide); sulfonylureas (e.g., glimepiride, glyburide andglipizide); biguanide/glyburide combinations (e.g., GLUCOVANCE®),thiozolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone),PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dualagonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein(aP2) such as those disclosed in WO 00/59506, glucagon-like peptide-1(GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors.

Examples of suitable anti-depressant agents for use in combination withthe compounds of the present invention include nefazodone andsertraline.

Examples of suitable anti-inflammatory agents for use in combinationwith the compounds of the present invention include: prednisone;dexamethasone; ENBREL®; protein tyrosine kinase (PTK) inhibitors;cyclooxygenase inhibitors (including NSAIDs, and COX-1 and/or COX-2inhibitors); aspirin; indomethacin; ibuprofen; prioxicam; naproxen;celecoxib; and/or rofecoxib.

Examples of suitable anti-osteoporosis agents for use in combinationwith the compounds of the present invention include alendronate andraloxifene.

Examples of suitable hormone replacement therapies for use incombination with the compounds of the present invention include estrogen(e.g., congugated estrogens) and estradiol.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include orlistat and aP2 inhibitors(such as those disclosed in WO 00/59506).

Examples of suitable anti-anxiety agents for use in combination with thecompounds of the present invention include diazepam, lorazepam,buspirone, and hydroxyzine pamoate.

Examples of suitable anti-anxiety agents for use in combination with thecompounds of the present invention include diazepam, lorazepam,buspirone, and hydroxyzine pamoate.

Examples of suitable anti-proliferative agents for use in combinationwith the compounds of the present invention include cyclosporin A,paclitaxel, adriamycin; epithilones, cisplatin, and carboplatin.

Examples of suitable anti-ulcer and gastroesophageal reflux diseaseagents for use in combination with the compounds of the presentinvention include famotidine, ranitidine, and omeprazole.

Administration of the compounds of the present invention (i.e., a firsttherapeutic agent) in combination with at least one additionaltherapeutic agent (i.e., a second therapeutic agent), preferably affordsan efficacy advantage over the compounds and agents alone, preferablywhile permitting the use of lower doses of each. A lower dosageminimizes the potential of side effects, thereby providing an increasedmargin of safety. It is preferred that at least one of the therapeuticagents is administered in a sub-therapeutic dose. It is even morepreferred that all of the therapeutic agents be administered insub-therapeutic doses. Sub-therapeutic is intended to mean an amount ofa therapeutic agent that by itself does not give the desired therapeuticeffect for the condition or disease being treated. Synergisticcombination is intended to mean that the observed effect of thecombination is greater than the sum of the individual agentsadministered alone.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of thrombin, Factor VIIa, IXa,Xa, XIa, and/or plasma kallikrein. Such compounds may be provided in acommercial kit, for example, for use in pharmaceutical researchinvolving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein.XIa. For example, a compound of the present invention could be used as areference in an assay to compare its known activity to a compound withan unknown activity. This would ensure the experimentor that the assaywas being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein. For example, the presence of thrombin, Factor VIIa, IXa, XaXIa, and/or plasma kallikrein in an unknown sample could be determinedby addition of the relevant chromogenic substrate, for example S2366 forFactor XIa, to a series of solutions containing test sample andoptionally one of the compounds of the present invention. If productionof pNA is observed in the solutions containing test sample, but not inthe presence of a compound of the present invention, then one wouldconclude Factor XIa was present.

Extremely potent and selective compounds of the present invention, thosehaving K_(i) values less than or equal to 0.001 μM against the targetprotease and greater than or equal to 0.1 μM against the otherproteases, may also be used in diagnostic assays involving thequantitation of thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein in serum samples. For example, the amount of Factor XIa inserum samples could be determined by careful titration of proteaseactivity in the presence of the relevant chromogenic substrate, S2366,with a potent and selective Factor XIa inhibitor of the presentinvention.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a thromboembolic and/or inflammatorydisorder (as defined previously). In another embodiment, the packageinsert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat a thromboembolic and/or inflammatory disorder. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

DOSAGE AND FORMULATION

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of the present invention and about 1 to7.5 milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where the compounds of the present invention are administered incombination with an anti-platelet agent, by way of general guidance,typically a daily dosage may be about 0.01 to 25 milligrams of thecompound of the present invention and about 50 to 150 milligrams of theanti-platelet agent, preferably about 0.1 to 1 milligrams of thecompound of the present invention and about 1 to 3 milligrams ofantiplatelet agents, per kilogram of patient body weight.

Where the compounds of the present invention are administered incombination with thrombolytic agent, typically a daily dosage may beabout 0.1 to 1 milligrams of the compound of the present invention, perkilogram of patient body weight and, in the case of the thrombolyticagents, the usual dosage of the thrombolyic agent when administeredalone may be reduced by about 70-80% when administered with a compoundof the present invention.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of the present invention, generally theamount of each component in a typical daily dosage and typical dosageform may be reduced relative to the usual dosage of the agent whenadministered alone, in view of the additive or synergistic effect of thetherapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

What is claimed is:
 1. A compound of Formula (V):

or its stereoisomers, tautomers, a pharmaceutically acceptable salts, orsolvates thereof, wherein: A is C₃₋₈ cycloalkyl substituted with 0-1 R¹and 0-3 R²— X¹, X², and X³ are independently CR³, CR⁴, CR⁴R⁵, N, NR³,NR⁶ or C(O); provided that

is a triazole Z is —C(R¹¹)(R¹²)—, or —C(R¹¹)(R¹²)—(CH₂)— L is —C(O)NR¹⁰—R¹ is, independently at each occurrence, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃alkyl)₂, —C(═NH)NH₂, —C(O)NR⁸R⁹, —S(O)_(p)NR⁸R⁹, —(CH₂)_(r)NR⁷R⁸,—(CH₂)_(r)NR⁷C(O)OR^(a), —CH₂NH₂, CH₂NH(C₁₋₃ alkyl), —CH₂N(C₁₋₃ alkyl)₂,—CH₂CH₂NH₂, —CH₂CH₂NH(C₁₋₃ alkyl), —CH₂CH₂N(C₁₋₃ alkyl)₂, —CH(C₁₋₄alkyl)NH₂, —C(C₁₋₄ alkyl)₂NH₂, —C(═NR^(8a))NR⁷R⁸, —NHC(═NR^(8a))NR⁷R⁸,═NR⁸, —NR⁸CR⁸(═NR^(8a)), F, Cl, Br, I, OCF₃, CF₃, —(CH₂)_(r)OR^(a),—(CH₂)_(r)SR^(a), CN, 1-NH₂-1-cyclopropyl, or C₁₋₆ alkyl substitutedwith 0-1 R^(1a); R^(1a) is H, —C(═NR^(8a))NR⁷R⁸, —NHC(═NR^(8a))NR⁷R⁸,—NR⁸CH(═NR^(8a)), —NR⁷R⁸, —C(O)NR⁸R⁹, F, OCF₃, CF₃, OR^(a), SR^(a), CN,—NR⁹SO₂NR⁸R⁹, —NR⁸SO₂R^(c), —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, or—(CF₂)_(r)CF₃; R² is, independently at each occurrence, H, ═O, F, Cl,Br, I, OCF₃, CF₃, CHF₂, CN, NO₂, OR^(a), SR^(a), —C(O)R^(a),—C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b),—S(O)₂NR⁸R⁹, —NR⁸S(O)₂R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkylsubstituted with 0-2 R^(2a), C₂₋₆ alkenyl substituted with 0-2 R^(2a),C₂₋₆ alkynyl substituted with 0-2 R^(2a), —(CH₂)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(2b), or —(CH₂)_(r)-5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(2b);R^(2a) is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸,CN, OCF₃, CF₃, OR^(a), SR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸SO₂R_(c), —S(O)R^(c), or —S(O)₂R^(c); R^(2b) is,independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸, CN, NO₂,OR^(a), SR^(a), —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸,—C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —S(O)₂NR⁸R⁹, —S(O)₂R^(c), —NR⁸SO₂NR⁸R⁹,—NR⁸SO₂R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄ haloalkoxy; alternately, whenR¹ and R² groups are substituted on adjacent ring atoms, they can betaken together with the ring atoms to which they are attached to form a5- to 7-membered carbocycle or heterocycle comprising: carbon atoms and0-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidcarbocycle or heterocycle is substituted with 0-2 R^(2b); R³ is,independently at each occurrence, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)C(O)NR⁸(CH₂)_(s)CO₂R^(3b), —(CH₂)_(r)CO₂R^(3b),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(3a) and 0-1 R^(3d),or —(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(3a) and 0-1 R^(3d); R^(3a) is,independently at each occurrence, ═O, F, Cl, Br, I, OCF₃, CF₃, NO₂, CN,—(CH₂)_(r)OR^(3b), —(CH₂)_(r)SR^(3b), —(CH₂)_(r)NR⁷R⁸, C(═NR^(8a))NR⁸R⁹,—NHC(═NR^(8a))NR⁷R⁸, —NR⁸CR⁸(═NR^(8a)), —(CH₂)_(r)NR⁸C(O)R^(3b), ═NR⁸,—(CH₂)_(r)NR⁸C(O)R^(3b), —(CH₂)_(r)NR⁸C(O)₂R^(3b),—(CH₂)_(r)S(O)_(p)NR⁸R⁹, —(CH₂)_(r)NR⁸S(O)_(p)R^(3c), —S(O)_(p)R^(3c),—S(O)_(p)R^(3c), —C(O)—C₁₋₄ alkyl, —(CH₂)_(r)CO₂R^(3b),—(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(r)OC(O)NR⁸R⁹, —NHCOCF₃, —NHSO₂CF₃, —SO₂NHR^(3b), —SO₂NHCOR^(3c), —SO₂NHCO₂R^(3c), —CONHSO₂R^(3c), —NHSO₂R^(3c),—CONHOR^(3b), C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy-, C₁₋₆ alkyl substitutedby R^(3d), C₂₋₆ alkenyl substituted by R^(3d), C₂₋₆ alkynyl substitutedby R^(3d), C₃₋₆ cycloalkyl substituted by 0-1 R^(3d), —(CH₂)_(r)—C₃₋₁₀carbocycle substituted with 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-3R^(3d); alternately, when two R^(3a) groups are located on adjacentatoms, they can be taken together with the atoms to which they areattached to form a C₃₋₁₀ carbocycle substituted with 0-2 R^(3d) or a 5-to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(3d); R^(3b) is, independently at eachoccurrence, H, C₁₋₆ alkyl substituted with 0-2 R^(3d), C₂₋₆ alkenylsubstituted with 0-2 R^(3d), C₂₋₆ alkynyl substituted with 0-2 R^(3d),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(3d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(3d); R^(3c) is, independently ateach occurrence, C₁₋₆ alkyl substituted with 0-2 R^(3d), C₂₋₆ alkenylsubstituted with 0-2 R^(3d), C₂₋₆ alkynyl substituted with 0-2 R^(3d),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(3d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(3d); R^(3d) is, independently ateach occurrence, H, ═O, —(CH₂)_(r)OR^(a), F, Cl, Br, CN, NO₂,—(CH₂)_(r)NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁷C(O)R^(b),—C(O)NR⁸R⁹, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂R^(c), —S(O)_(p)R^(c),—(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e), C₂₋₆ alkenylsubstituted with 0-2 R^(e), C₂₋₆ alkynyl substituted with 0-2 R^(e),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5-to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(d); R⁴ is, independently at each occurrence, H,═O, F, Cl, Br, I, OCF₃, CF₃, OR^(a), SR^(a), CN, NO₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkylsubstituted with 0-2 R^(4a), C₂₋₆ alkenyl substituted with 0-2 R^(4a),C₂₋₆ alkynyl substituted with 0-2 R^(4a), —(CH₂)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(4b), or —(CH₂)_(r)-5- to 10-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(4b);R^(4a) is, independently at each occurrence, H, F, ═O, C₁₋₆ alkyl,OR^(a), SR^(a), CF₃, CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)₂R^(c),—S(O)R^(c), or —S(O)₂R^(c); R^(4b) is, independently at each occurrence,H, ═O, ═NR⁸, F, Cl, Br, I, OR^(a), SR^(a), CN, NO₂, CF₃, —SO₂R^(c),—NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁷R⁸, —C(O)NR⁸R⁹,—NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄ haloalkoxy-; alternately, R³and R⁴ groups when located on adjacent atoms, can be taken together toform a C₃₋₁₀ carbocycle substituted with 0-2 R^(3d) or a 5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(3d); R⁵ is, independently at each occurrence, H,F, OCF₃, CF₃, OR^(a), SR^(a), CN, NO₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)R^(a), —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)₂R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2R^(5a), C₂₋₆ alkenyl substituted with 0-2 R^(5a), C₂₋₆ alkynylsubstituted with 0-2 R^(5a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(5b), or —(CH₂)_(r)-5-10 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(5b); R^(5a) is,independently at each occurrence, H, ═O, OR^(a), SR^(a), F, Cl, Br, I,CF₃, OCF₃, CN, NO₂, —NR⁷R⁸, —NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b),—S(O)₂NR⁸R⁹, —NR⁸S(O)₂R^(c), —S(O)R^(c), or —S(O)₂R^(c); R^(5b) is,independently at each occurrence, H, ═O, ═NR⁸, F, Cl, Br, I, OR^(a),SR^(a), CN, NO₂, CF₃, —SO₂R^(c), —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a),—OC(O)R^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)₂NR⁸R⁹,—S(O)₂R^(c), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,C₁₋₄ haloalkyl, or C₁₋₄ haloalkoxy-; R⁶ is, independently at eachoccurrence, H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, —CH₂OR^(a), —C(O)R^(c),—C(O)₂R^(c), —S(O)₂R^(c), or —(CH₂)_(r)-phenyl substituted with 0-3R^(d); R⁷ is, independently at each occurrence, H, C₁₋₆ alkyl,—(CH₂)_(n)—C₃₋₁₀ carbocycle, —(CH₂)_(n)-(5-10 membered heteroaryl),—C(O)R^(c), —CHO, —C(O)₂R^(c), —S(O)₂R^(c), —CONR⁸R^(c), —OCONHR^(c),—C(O)O—(C₁₋₄ alkyl)OC(O)—(C₁₋₄ alkyl), or —C(O)O—(C₁₋₄alkyl)OC(O)—(C₆₋₁₀ aryl); wherein said alkyl, carbocycle, heteroaryl,and aryl are optionally substituted with 0-2 R^(f); R⁸ is, independentlyat each occurrence, H, C₁₋₆ alkyl, or —(CH₂)_(r)-phenyl, or—(CH₂)_(n)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p); wherein said alkyl, phenyland heterocycle are optionally substituted with 0-2 R^(f);alternatively, R⁷ and R⁸, when attached to the same nitrogen, combine toform a 5- to 10-membered heterocyclic ring comprising carbon atoms and0-2 additional heteroatoms selected from N, O, and S(O)_(p), whereinsaid heterocycle is substituted with 0-2 R^(d); R^(8a) is, independentlyat each occurrence, H, OH, C₁₋₆ alkyl, C₁₋₄ alkoxy, (C₆₋₁₀ aryl)-C₁₋₄alkoxy, —(CH₂)_(n)-phenyl, —(CH₂)_(n)-(5-10 membered heteroaryl),—C(O)R^(c), —C(O)₂R^(c), —C(O)O—(C₁₋₄ alkyl)OC(O)—(C₁₋₄ alkyl), or—C(O)O—(C₁₋₄ alkyl)OC(O)—(C₆₋₁₀ aryl); wherein said phenyl, aryl, andheteroaryl is optionally substituted with 0-2 R^(f); R⁹ is,independently at each occurrence, H, C₁₋₆ alkyl, or —(CH₂)_(n)-phenyl;wherein said alkyl and phenyl are optionally substituted with 0-2 R^(f);R^(9a) is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl; alternatively, R⁸ and R⁹, when attached to the samenitrogen, combine to form a 5- to 10-membered heterocyclic ringcomprising carbon atoms and 0-2 additional heteroatoms selected from N,O, and S(O)_(p), wherein said heterocycle is substituted with 0-2 R^(d);R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-3 R^(10a), C₂₋₆ alkenyl substituted with 0-3 R^(10a), C₂₋₆ alkynylsubstituted with 0-3 R^(10a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(d); R^(10a) is,independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a), SR^(a), F,CF₃, CN, NO₂, —C(O)OR^(a), —NR⁷R⁸, —C(O)NR⁷R⁸, —NR₇C(O)R^(b),S(O)_(p)NR⁸R⁹, —NR⁸SO₂R^(c)—, —S(O)R^(c), or —S(O)₂R^(c); R¹¹ is C₁₋₄haloalkyl, —(CH₂)_(r)C(O)NR⁸R⁹, C₁₋₆ alkyl substituted with 0-3 R^(11a),C₂₋₆ alkenyl substituted with 0-3 R^(11a), C₂₋₆ alkynyl substituted with0-3 R^(11a), —(CR¹⁴R¹⁵)_(r)—C₃₋₁₀ carbocycle substituted with 0-3R^(11b), or —(CR¹⁴R¹⁵)_(r)-5- to 10-membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(11b); R^(11a) is,independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a), CF₃,SR^(a), F, CN, NO₂, NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —C(O)R^(a), —C(O)OR^(a), —S(O)_(p)R^(c), C₃₋₆cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy-, —(CH₂)_(r)—C₃₋₁₀carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p), and substituted with 0-3 R^(d); R^(11b) is,independently at each occurrence, H, ═O, ═NR⁸, OR^(a), F, Cl, Br, CN,NO₂, CF₃, OCF₃, OCHF₂, —C(O)R^(a), —C(O)OR^(a), —SOR^(c), —SO₂R^(c),—NR⁷R⁸, —C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —NR⁸C(O)₂R, —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy-, —(CH₂)_(r)—C₃₋₁₀carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5-10 memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-3R^(d); alternately, when two R^(11b) groups are substituents on adjacentatoms they may be taken together with the atoms to which they areattached to form a 5- to 7-membered heterocycle comprising carbon atomsand 1-4 heteroatoms selected from N, O, and S(O)_(p) and substitutedwith 0-2 R^(g); R¹² is, independently at each occurrence, H, F, or C₁₋₄alkyl; R¹⁴ and R¹⁵ are, independently at each occurrence, H, F, or C₁₋₄alkyl; alternately, R¹⁴ combines with R¹⁵ to form ═O; R^(a) is,independently at each occurrence, H, CF₃, C₁₋₆ alkyl, —(CH₂)_(r)—C₃₋₇cycloalkyl, —(CH₂)_(r)—C₆₋₁₀ aryl, or —(CH₂)_(r)-5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p); wherein said cycloalkyl, aryl and heteroaryl groupsare optionally substituted with 0-2 R^(f); R^(b) is, independently ateach occurrence, CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, —(CH₂)_(r)—C₃₋₁₀carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5-10 memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-3R^(d); R^(c) is, independently at each occurrence, CF₃, C₁₋₆ alkylsubstituted with 0-2 R^(f), C₃₋₆ cycloalkyl substituted with 0-2 R^(f),C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, (C₆₋₁₀ aryl)-C₁₋₄ alkyl, or(5- to 10-membered heteroaryl)-C₁₋₄ alkyl, wherein said aryl andheteroaryl groups are optionally substituted with 0-3 R^(f); R^(d) is,independently at each occurrence, H, ═O, ═NR⁸, OR^(a), F, Cl, Br, I, CN,NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁸C(O)R^(a),—C(O)NR⁷R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl, —NR⁸SO₂CF₃,—NR⁸SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl,—(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e), C₂₋₆ alkenylsubstituted with 0-2 R^(e), or C₂₋₆ alkynyl substituted with 0-2 R^(e);R^(e) is, independently at each occurrence, ═O, OR^(a), F, Cl, Br, I,CN, NO₂, —NR⁸R⁹, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁸C(O)R^(a),—C(O)NR⁷R⁸, —SO₂NR⁸R⁹, NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl, —NR⁸SO₂CF₃,—NR⁸SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, or—(CF₂)_(r)CF₃; R^(f) is, independently at each occurrence, H, ═O,—(CH₂)_(r)—OR^(g), F, Cl, Br, I, CN, NO₂, —NR^(9a)R^(9a), —C(O)R^(g),—C(O)OR^(g), —NR^(9a)C(O)R^(g), —C(O)NR^(9a)R^(9a), —SO₂NR^(9a)R^(9a),—NR^(9a)SO₂NR^(9a)R^(9a), —NR^(9a)SO₂—C₁₋₄ alkyl, —NR^(9a)SO₂CF₃,—NR^(9a)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)-C₁₋₄ alkyl, —S(O)_(p)-phenyl,—(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, or—(CH₂)_(n)-phenyl; R^(g) is, independently at each occurrence, H, C₁₋₆alkyl, or —(CH₂)_(n)-phenyl; n, at each occurrence, is selected from 0,1, 2, 3, and 4; p, at each occurrence, is selected from 0, 1, and 2; r,at each occurrence, is selected from 0, 1, 2, 3, and 4; and s, at eachoccurrence, is selected from 1, 2, 3, and
 4. 2. A compound according toclaim 1, wherein: A is C₃₋₈ cycloalkyl substituted with 0-1 R¹ and 0-3R², Z is —C(R¹¹)(R¹²)—; L is —C(O)NR¹⁰; R³ is, independently at eachoccurrence, —(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(r)C(O)NR(CH₂)_(s)CO₂R^(3b),(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)—C₃₋₈ cycloalkyl substituted with 0-2R^(3a) and 0-1 R^(3d), —(CH₂)_(r)-phenyl substituted with 0-3 R^(3a) andR^(3d), —(CH₂)_(r)-naphthyl substituted with 0-3 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-indanyl substituted with 0-3 R^(3a) and 0-1 R^(3d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(3a) and 0-1 R^(3d); R⁴ is H, F, Cl, Br, I,OCF₃, CF₃, OR^(a), SR^(a), CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —NR⁷R⁸,—C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(4a), C₂₋₆alkenyl substituted with 0-2 R^(4a), C₂₋₆ alkynyl substituted with 0-2R^(4a), phenyl substituted with 0-2 R^(4b), or a 5-10 memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-3R^(4b); R⁶ is, independently at each occurrence, H, C₁₋₆ alkyl,—CH₂OR^(a), —C(O)R^(c), —C(O)₂R^(c), or —(CH₂)_(r)-phenyl substitutedwith 0-3 R^(d); R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkylsubstituted with 0-3 R^(10a), —(CH₂)_(r)-phenyl substituted with 0-3R^(d), or —(CH₂)_(r)-5-10 membered heterocycle comprising carbon atomsand 1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(d); and R¹¹ is C₁₋₄ haloalkyl,—(CH₂)_(r)C(O)NR⁸R⁹, C₁₋₆ alkyl substituted with 0-3 R^(11a), C₂₋₆alkenyl substituted with 0-3 R^(11a), C₂₋₆ alkynyl substituted with 0-3R^(11a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(11b), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(11b).
 3. A compound according to claim 1,wherein: A is C₅₋₆ cycloalkyl substituted with 0-1 R¹ and 0-2 R²; R³ is,independently at each occurrence, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)C(O)NR(CH₂)_(s)CO₂R^(3b), —(CH₂)_(r)CO₂R^(3b),—(CH₂)_(r)-phenyl substituted with 0-3 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-naphthyl substituted with 0-3 R^(3a) and 0-1 R^(3d),—(CH₂)_(r)-indanyl substituted with 0-3 R^(3a) and 0-1 R^(3d), or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(3a) and 0-1 R^(3d); and R⁶ is, independentlyat each occurrence, H or C₁₋₆ alkyl.
 4. A compound according to claim 1,wherein: the group

is selected from:


5. A compound according to claim 1, wherein: A is substituted with 0-1R¹ and 0-2 R² and selected from: C₃₋₇ cycloalkyl; the group

is selected from:

Z is —CH(R¹¹)—; L is —C(O)NR¹⁰; R³ is, independently at each occurrence,—(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(r)C(O)NR⁸(CH₂)_(s)CO₂R^(3b),—(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)-phenyl substituted with 0-3 R^(3a) and0-1 R^(3d), —(CH₂)_(r)-naphthyl substituted with 0-3 R^(3a) and 0-1R^(3d), —(CH₂)_(r)-indanyl substituted with 0-3 R^(3a) and 0-1 R^(3d) or—(CH₂)_(r)-5-10 membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), and substituted with 0-3R^(3a) and 0-1 R^(3d); R⁴ is, independently at each occurrence, H, ═O,F, Cl, Br, I, OCF₃, CF₃, CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —NR⁷R⁸,—C(O)NR⁸R⁹, —NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(4a), C₂₋₆alkenyl substituted with 0-2 R^(4a), C₂₋₆ alkynyl substituted with 0-2R^(4a), phenyl substituted with 0-2 R^(4b), or a 5-10 memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), and substituted with 0-3 R^(4b); R⁶ is H, C₁₋₆alkyl, or —(CH₂)_(r)-phenyl substituted with 0-3 R^(d); and R¹⁰ is,independently at each occurrence, H, C₁₋₆ alkyl substituted with 0-2R^(10a), —(CH₂)_(r)-phenyl substituted with 0-2 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(d).
 6. A compound according to claim 1,wherein the compound is of Formula (VI):

or its stereoisomers, tautomers, pharmaceutically acceptable salts, orsolvates thereof, within the scope of the eighteenth aspect wherein: R³is —(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(s)C(O)NR(CH₂)_(r)CO₂R^(3b),—(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)-phenyl substituted with 0-3 R^(3a) and0-1 R^(3d), —(CH₂)_(r)-naphthyl substituted with 0-2 R^(3a),—(CH₂)_(r)-indanyl substituted with 0-2 R^(3a), or —(CH₂)_(r)-5-10membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(3a) and 0-1 R^(3d); R⁶ is, independently at eachoccurrence, H, C₁₋₆ alkyl, —CH₂OR^(a), —C(O)R^(c), —C(O)₂R^(c), or—(CH₂)_(r)-phenyl substituted with 0-3 R^(d); R¹⁰ is, independently ateach occurrence, H, C₁₋₆ alkyl substituted with 0-3 R^(10a),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(d); and R¹¹ is C₁₋₄ haloalkyl,—(CH₂)_(r)C(O)NR⁸R⁹, C₁₋₆ alkyl substituted with 0-3 R^(11a), C₂₋₆alkenyl substituted with 0-3 R^(11a), C₂₋₆ alkynyl substituted with 0-3R^(11a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(11b), or—(CH₂)_(r)-5-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(11b).
 7. A compound according to claim 6,wherein: R¹ is, independently at each occurrence, F, Cl, Me, Et, —NH₂,—C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂NHCO₂Bn, —CH₂NHCO₂(t-Bu),—CH(Me)NH₂, —CMe₂NH₂, —NHEt, —NHCO₂(t-Bu), —NHCO₂Bn, —SO₂NH₂, OR^(a), or—CH₂R^(1a); R³ is —CO₂H, —CO₂Me, —C(O)NHCH₂CO₂H, —C(O)NHCH₂CO₂Et,—C(O)NH₂, —C(O)NHMe, —C(O)NHBn, —(CH₂)_(r)-phenyl substituted with 0-2R^(3a) and 0-1 R^(3d), naphthyl substituted with 0-2 R^(3a) and 0-1R^(3d), indanyl substituted with 0-2 R^(3a) and 0-1 R^(3d), or a—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-2 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-2 R^(3a) and 0-1 R^(3d); R⁶ is H; R¹⁰is, independently at each occurrence, H, Me, benzyl, phenethyl,—CH₂CH₂CO₂H, —CH₂CH₂CO₂Me, —CH₂CH₂CO₂Et, —CH₂CH₂CONH₂, or—CH₂CH₂CONHCH₂CH₂Ph; and R¹¹ is C₁₋₆ alkyl, —CH₂CONR⁸R⁹, —CH₂CH₂CONR⁸R⁹,—CH₂OBn, —CH₂SBn, —(CH₂)_(r)—C₃₋₇ cycloalkyl substituted with 0-2R^(11b), —(CH₂)_(r)-phenyl substituted with 0-2 R^(11b),—(CH₂)_(r)-naphthyl substituted with 0-2 R^(11b), or —(CH₂)_(r)-5-10membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(11b).
 8. A compound according to claim 1,wherein the compound is of Formula (VII):

or its stereoisomers, tautomers, pharmaceutically acceptable salts, orsolvates thereof, A is substituted with 0-2 R¹ and 0-1 R² and selectedfrom: C₃₋₇ cycloalkyl; L is —C(O)NH—; R¹ is, independently at eachoccurrence, F, Cl, Me, Et, —NH₂, —C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂,—CH₂NHCO₂Bn, —CH₂NHCO₂(t-Bu), —CH(Me)NH₂, —CMe₂NH₂, —NHEt, —NHCO₂(t-Bu),—NHCO₂Bn, —SO₂NH₂, OR^(a), or —CH₂R^(1a); R³ is —CO₂H, —CO₂Me,—C(O)NHCH₂CO₂H, —C(O)NHCH₂CO₂Et, —C(O)NH₂, —C(O)NHMe, —C(O)NHBn, phenylsubstituted with 0-2 R^(3a), naphthyl substituted with 0-2 R^(3a),indanyl substituted with 0-2 R^(3a), or a 5- to 10-membered heterocyclecomprising: carbon atoms and 1-2 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-2 R^(3a); R⁴ isH, F, Cl, Br, CF₃, CO₂H, CO₂Me, CO₂Et, C₁₋₆ alkyl substituted with 0-2R^(4a), phenyl substituted with 0-2 R^(4b), or 5-10 membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-2 R^(4b); R¹¹is C₁₋₆ alkyl, —CH₂CONR⁸R⁹, —CH₂CH₂CONR⁸R⁹, —CH₂OBn, —CH₂SBn,—(CH₂)_(r)—C₃₋₇ cycloalkyl substituted with 0-2 R^(11b),—(CH₂)_(r)-phenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-naphthylsubstituted with 0-2 R^(11b), or —(CH₂)_(r)-5- to 10-membered heteroarylsubstituted with 0-2 R^(11b) and selected from thiazolyl, oxazolyl,triazolyl, tetrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,benzimidazolyl, benzothiazolyl, quinolinyl, and isoquinolinyl; R^(11b)is, independently at each occurrence, H, F, Cl, Br, CF₃, OMe, OEt,O(i-Pr), OCF₃, OCHF₂, CN, OPh, OBn, NO₂, —NH₂, —C(O)R^(a), —C(O)OR^(a),—C(O)NR⁷R⁸, —NR⁷C(O)R^(b), —NR⁸C(O)₂R^(c), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —SO₂R^(c), C₁-C₄-alkyl, Ph, or Bn; and alternately,when two R^(11b) groups are substituents on adjacent atoms they may betaken together with the atoms to which they are attached to form a 5- to7-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p) and substituted with 0-2 R^(g).
 9. Acompound according to claim 8, wherein: A is 4-CH₂NH₂-cyclohexyl; and R³is phenyl, 3-CN-phenyl, 4-CN-phenyl, 3-Br-phenyl, 4-Br-phenyl,3-OMe-phenyl, 4-OMe-phenyl, 3-CF₃-phenyl, 4-CF₃-phenyl, 3-CO₂H-phenyl,4-CO₂H-phenyl, 4-CO₂Me-phenyl, 4-CH₂CO₂H-phenyl, 4-CH₂CO₂Me-phenyl,3-CONH₂-phenyl, 4-CONH₂-phenyl, 4-CONHMe-phenyl, 4-CON(Me)₂-phenyl,4-CH₂CONH₂-phenyl, 4-amidino-phenyl, or 2,4-diF-phenyl.
 10. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim 1.